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Successes and Failures of Combined Modality Therapies in Head and Neck Cancer
Author’s Accepted Manuscript Successes and Failures of Combined Modality Therapies in Head and Neck Cancer Daniel W. Bowles, Eric Deutsch, David Raben
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S1053-4296(16)30015-7 http://dx.doi.org/10.1016/j.semradonc.2016.05.004 YSRAO50553
To appear in: Seminars in Radiation Oncology Cite this article as: Daniel W. Bowles, Eric Deutsch and David Raben, Successes and Failures of Combined Modality Therapies in Head and Neck Cancer, Seminars in Radiation Oncology, http://dx.doi.org/10.1016/j.semradonc.2016.05.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Successes and Failures of Combined Modality Therapies in Head and Neck Cancer
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Daniel W. Bowles, M.D., 3Eric Deutsch, M.D., Ph.D., M.D. and 4David Raben, M.D.
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Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO
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Department of Medicine, Denver Veterans Affairs Medical Center, Denver, CO
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Department of Molecular Radiotherapy, Gustave Roussy Cancer Campus, Paris, France.
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Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO
Address inquiries and reprint requests to: David Raben, MD, Department of Radiation Oncology, University of Colorado Health, Mail Stop F706, 1665 Aurora Court, Suite 1032, Aurora, CO80045. E-mail: [email protected]
ABSTRACT The paradigms for treating head and neck squamous cell carcinoma are changing as new subgroups are defined. The technical successes of improved radiation therapy are many; however, the success of novel combined therapies are few. With the emergence of human papillomavirus (HPV) and the development of immuno-oncology agents, such as checkpoint inhibitors, are we ready to reevaluate how we use radiation and chemotherapy for locally advanced and metastatic disease – will we remain the fire or become the fire starter?
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Introduction Success or failure in the management of head and neck squamous cell carcinoma (HNSCC) over the past several decades is in the eye of the beholder – as well as in the results of phase 3 trials. After establishing the role of combined cisplatin-based combined chemotherapy and radiation more than three decades ago [1, 2], the acute and long term side effects of curative-intent therapy remain problematic and 5-year overall survival (OS) for non-human papillomavirus (HPV)-driven HNSCC remains poor [3, 4]. New sensitizers, such as the taxanes and/or anti-epidermal growth factor receptor (EGFR) antibodies, are being employed with hopes that they may improve outcomes [5]. Similarly, functional outcomes have improved as radiation techniques have advanced over the past 15 years, yet much more needs to be done. We are now entering a new world with advanced radiation techniques, novel small molecule inhibitors such DNA repair inhibitors, PI3K inhibitors, mTOR inhibitors, and now the burgeoning world of immuno-oncology. Will these new agents and techniques lead to the success we are looking for and will our view of combined modality therapy shift? To help us decide the best way forward in definitive HNSCC management, this review article will review select recent successes and failures in combined modality therapy and provide some thoughts for the future.
It’s Technical: Radiation Success with Improved Planning and Delivery Capabilities Dramatic improvements in radiation software and hardware have enabled radiation oncologists to make the shift from a 3-D to a more elegant intensity modulated radiation therapy (IMRT) world. While not the focus of the review, we would be remiss not to mention how the adoption of IMRT has improved functional outcomes for HNSCC patients. For instance, sparing of the constrictor muscles, mylo/geniohyoid complex and the esophageal inlet, and understanding that reducing the volume of normal tissue exposed to doses greater than 60 Gy reduces long term dysphagia, has been an important achievement [6-8]. We continue to explore a variety of delivery techniques such as volumetricmodulated arc therapy (VMAT) or TOMOtherapy to maximize normal tissue sparing while sending homogenous doses of radiation to the intended targets. Salivary function and quality of life continue to improve as radiation oncologists use parotid and submandibular sparing techniques with no decrease in safety [9-11]. Beyond decreasing long term side effects, IMRT-based approaches may also improve cancer specific survival [12]. Novel radiation techniques may push the envelope further with regards to efficacy and toxicity. For instance, will proton beam radiation therapy take us further down the reduced toxicity pathway? Proton beam radiation therapy reduces acute toxicity compared with IMRT for head and neck tumors that require ipsilateral radiation, but its effect on long term toxicities are unknown [13, 14]. Stereotactic body radiation therapy may allow for more rapid and safe delivery of radiation to he head and neck area similar to what we have achieved in other sites like prostate and pancreas. Time and rigorous comparisons between proton and photon therapy in HNSCC treatment will determine whether protons will be a future success story.
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The Failure of Neoadjuvant Chemotherapy: Revisiting the Past to see the Future Our goal in this section is not to belabor the failures of neoadjuvant/induction chemotherapy but to drive home the point that this strategy has been investigated extensively in both the organ preservation and pre-operative settings, yet no clear improvements in patient outcomes have been demonstrated. The central theory of neoadjuvant chemotherapy, also referred to as sequential or induction chemotherapy, is that multi-agent chemotherapy given at the beginning of curative-intent therapy can improve OS by improving local-regional control (LRC) and decreasing distant metastatic recurrence. The widespread adoption of neoadjuvant chemotherapy followed by radiation can be traced to the landmark Department of Veterans Affairs Larynx Preservation trial published 25 years ago which demonstrated that neoadjuvant chemotherapy with cisplatin and 5-fluorouracil [FU] (PF) followed by radiation yielded similar survival to laryngectomy followed by radiation in select larynx cancer patients but with improved organ preservation [15]. RTOG 91-11 subsequently demonstrated that concurrent CRT improved organ preservation rates but not OS compared to neoadjuvant chemotherapy followed by RT, however, and concurrent CRT became the standard of care [16]. Introduction of taxanes into the neoadjuvant regimens renewed enthusiasm in the mid-2000’s when TAX323 and TAX324 were published. These two randomized, phase 3 trials demonstrated that the addition of a taxane (docetaxel) to neoadjuvant cisplatin, and 5-FU (TPF) followed by either RT alone or concurrent low dose, weekly carboplatin plus RT yielded superior LRC, progression free survival (PFS), and OS compared to neoadjuvant PF in oropharynx, larynx, and hypopharynx cancers [17, 18]. The GORTEC trial subsequently demonstrated TPF’s superiority over PF followed by RT in larynx cancers and a large meta-analysis confirmed that TPF is a superior neoadjuvant regimen compared to PF [19, 20]. Neoadjuvant chemotherapy before standard of care definitive therapy. Did we achieve any success when we compared the above regimen to CRT or surgery followed by RT? “No” is the unfortunate answer. Several randomized trials have been published comparing neoadjuvant chemotherapy followed by standard of care definitive therapy (Table 1). A study from China administered TPF prior to surgical resection for oral cavity SCC versus surgery upfront and found that, while a complete response to TPF predicted improved OS, there was no OS difference between the entire TPF and non-TPF groups [21]. Two United States-based phase 3 trials, DeCIDE and PARADIGM, failed to demonstrate a clear benefit to neoadjuvant chemotherapy compared to concurrent CRT (Table 1) [22, 23]. Both of these studies randomized patients to CRT or CRT preceded by neoadjuvant TPF. In both studies there was no difference in OS between the two groups (hazard ratio [HR] 0.91; 95% confidence interval [CI] 0.59-1.91; p=0.68 in the DeCIDE trial; HR 1.09; 95% CI 0·59–2·03; p=0.77 in the PARADIGM trial) and no specific subgroup has experienced an OS benefit from neoadjuvant TPF. Adding to the lack of survival success was consistently higher toxicity in the neoadjuvant arms. A phase 3 study from Spain with a similar treatment plan to PARADIGM also failed to demonstrate an improvement in OS with neoadjuvant chemotherapy at the cost of excess toxicity (Table 1). While these studies lacked the statistical power to demonstrate improved OS due to poor accrual and/or longer than expected 3
survival in the control group, the results were disappointing and point to neoadjuvant chemotherapy’s shortcomings [24]. Are there any neoadjuvant success stories? The only randomized study to report an OS advantage to neoadjuvant chemotherapy was an ambitious 2x2 trial from Italy [25]. Patients were randomized to four arms: 1) concurrent PF and standard fraction RT; 2) cetuximab and concurrent RT; 3) TPF x 3 cycles followed by concurrent PF-RT; 4) TPF followed by cetuximab-RT. For the initial analysis, the two neoadjuvant arms were combined and compared to the two concurrent CRT arms, demonstrating an improvement in 3-year PFS (HR 0.73; 95%CI 0.57-0.94, p=0.015) and OS (HR 0.72; 95%CI 0.55-0.96; p=0.025) for neoadjuvant chemotherapy. A subgroup analysis suggested TPF followed by cetuximab-RT may be superior to the other regimens (HR 0.57; 95% CI 0.34-0.93); however, the power to make this conclusion was limited. Toxicity did not differ significantly between all 4 arms. While the results of this study are provocative, it should be noted that this has only been presented in abstract form. The French GORTEC trials (NCT01233843) will address this topic further; however, at this point neoadjuvant chemotherapy should not be routinely given for patients with locally advanced HNSCC.
Accelerated Chemo-Radiation Therapy: A Bridge to Far? There was excitement that accelerated radiation (RTOG 9003) combined with concurrent chemotherapy would improve LRC and OS. The phase 3 RTOG 0129 and the GORTEC 99-02 studies attempted to answer this question, comparing conventional cisplatin-RT to accelerated cisplatin-radiation (or accelerated radiation alone in GORTEC). Unfortunately, neither trial demonstrated any improvements in LRC, PFS, or OS [26, 27]. As a result, new studies looking at accelerated CRT are limited. Let us emphasize to our readers that accelerated radiation and hyperfractionated radiation are different strategies with different toxicities and biological effects as RTOG 9003 enlightened us. The latter approach is generally offered at a dose per fraction of 1.1-1.2 Gy twice daily to doses ranging from ~74.4 Gy to 81.6 Gy. Thus it does provide ~6-12% dose escalation benefit. One could argue that we have never really done a study of hyperfractionated CRT to conventional CRT. Speculation here but our sense is that this might provide incremental benefits but at what cost? Success in Radiation Dose De-escalation? Induction chemotherapy and accelerated CRT have not been highly successful as therapeutic intensification strategies in HNSCC. Perhaps as a result, many studies are now heading in the opposite direction, trying to find ways to safely de-escalate therapy in patients with favorable prognoses. Numerous studies have clearly demonstrated improved OS for patients in HPV-related HNSCC [28, 29]. A study from the University of North Carolina recently demonstrated excellent local control in HPVpositive patients using reduced doses of radiation (60 Gy) and cisplatin (30mg/m2 weekly) [30]. ECOG 1308 assigned patients to neoadjuvant cisplatin, paclitaxel, and cetuximab with hopes of reducing 4
macroscopic tumor volume. Patients with a complete response (CR) were treated with de-escalated radiation (54 Gy), whereas others received standard dose radiation (66-70 Gy). In patients obtaining a CR (71% of patients) followed by reduced RT, a 2-year PFS of 80% and 2-year OS of 93% was observed, compared to 65% and 87% in the non-CR group, respectively [31]. These hypothesis generating data suggest that there may be role for neoadjuvant chemotherapy to determine the feasibility of a reduced radiation dose. Investigators at Mr. Sinai are leading a randomized, phase 3 “Quarterback” trial (NCT01706939) in which patients who have a clinical or radiographic partial or complete response to three cycles of TPF are randomized to carboplatin plus low-dose (56 Gy) or standard dose (70 Gy) radiation. Success here will be an opportunity to move away from a “one size fits all” approach and dramatically reduce radiation dose in a select group of patients that respond well to neoadjuvant chemotherapy. Complete elimination of chemotherapy may be the next step for select HPV-positive oropharyngeal patients based on emerging single institution data [32]. The NRG has subsequently embarked on an ambitious study (HN002) to evaluate good prognosis oropharyngeal cancer patients with reduced dose radiation (60 Gy) alone versus reduced dose radiation (60 Gy) with weekly cisplatin (NCT02254278). Success in management of this distinct biologic entity will rest on additional understanding of the differences between HPV positive and negative disease as it relates to driver mutations, inflammatory or non-inflammatory phenotypes and prognostics biomarkers in the genomic arena [33]. Where Do We Stand With Radiation Modulators? Modifying radiation delivery and dose may be important ways to improve HNSCC therapy; however, improvements in sensitizing agents may also improve outcomes. Drugs that affect radiosensitivity by targeting key cell survival pathways are likely to affect both tumors and normal tissues. Therefore, the balance between the tumor versus normal tissue differential response to radiotherapy of any novel drug radiation combination must be considered in treatment development. To date, one of the main factors limiting the implementation of radiosensitizers and radioprotectors in clinical care has been the nonspecific mechanism of action of these agents. Improved understanding of the optimal way to combine radiosensitizers in the context of clinical realities is needed to selectively increase tumor cell killing and local control while minimally affecting normal tissues. Targeting signal transduction pathways – any successes? The identification of critical survival pathways that influence cell fate after irradiation has contributed to render molecular-targeted therapies an attractive approach to maximize the therapeutic ratio of radiotherapy. Several survival pathways are activated following ionizing radiation, including PI3K, mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), Hedgehog, and transforming growth factor-β (TGFβ) pathways [34-36]. In addition to regulating cell death, these pathways can affect the tumor microenvironment and sometimes activate DNA damage repair [37, 38] [39]. As a result, inhibition of these pathways has the potential to increase the response to ionizing radiation of cancer cells through multiple mechanisms. 5
Blocking alternative or complementary pathways to EGFR – PI3K-AKT and mTOR The PI3K–AKT pathway is activated by various mutations that are commonly found in cancer, including receptor tyrosine kinase activations, activating mutations in PI3K, loss of the tumor suppressor phosphatase and tensin homolog (PTEN) [40]. Importantly, and similar to EGFR, activation of the PI3K– AKT pathway contributes to radiation resistance. As a result, selective inhibitors of this pathway increase the radiosensitivity of cancer cells, and many drugs targeting this pathway are currently in preclinical development or in clinical trials [41]. The specific activating mutations in tumors must be considered when targeting the PI3K–AKT signaling pathway, as drugs that block signaling upstream of the mutant protein may not be effective. Downstream blockade of the PI3K pathway using mTOR inhibitors combined with radiotherapy has yielded controversial results in terms of safety in phase 1/2 series in lung [42] or HNSCC tumors [43], underscoring the need for further optimization. The clinical relevance of PI3K mutations and its relationship to HPV positive head and neck cancers remains to be determined [44]. Lest we get too excited, recent randomized phase 2 trials comparing PX-866, an irreversible PI3K inhibitor, plus docetaxel or cetuximab versus docetaxel or cetuximab failed to demonstrate any survival or response benefits in both HPV-positive and HPV-negative patients [45, 46].
EGFR inhibition – lessons learned In order to find success, perhaps we need to reflect critically on the disconnect between our “promising” pre-clinical studies and failed clinical trials with biologic modulators lumped in with cisplatin-radiation [47]. It has been a long and winding road of failed trials with EGFR inhibitors and CRT. As a brief background, EGFR is a tyrosine kinase that signals through RAS and PI3K pathways. EGFR is commonly overexpressed in HNSCC [48-50]. High EGFR expression is associated with poor response to radiation [49] or chemoradiotherapy [50] while EGFR inhibitors have been shown to sensitize tumors to cisplatin [51] or radiation.[52-54] . Like a broken record we talk about the only trial with a biologic agent to improve outcomes with radiation but it is all we have to date. Importantly, and with fortuitous hindsight, no chemotherapy was administered giving our field the opportunity to study in a pure sense, anti-EGFR therapy with radiation. This seminal phase 3 study of the anti-EGFR antibody, cetuximab, and radiation demonstrated durable improvements in OS compared to radiation alone [55]. However, digging deeper into this study one must consider the results in the setting of p16 (HPV) status. Cetuximab appeared to demonstrate a OS and LRC benefit irrespective of p16 status in patients with oropharyngeal cancer over radiotherapy alone, though the number of p16-positive patients was small [56]. In this trial, with the exception of EGFR inhibition-caused acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the control and the study arms. In sharp contrast, some cases of major toxicities encountered in HNSCC patients treated with radiotherapy and cetuximab have since been described and a recent study suggests the overall toxicity between cisplatin6
RT and cetuximab-RT are similar [57-59]. EGFR polymorphisms may correlate with major toxicities in cetuximab-RT [60], but this still remains controversial and does not constitute part of the routine pretherapeutic assessment of patients receiving cetuximab based CRT. We next followed the yellow brick road given cetuximab’s success as a radiation sensitizer, and “logically” compared cisplatin-RT to cetuximab plus cisplatin-RT in RTOG 0522. [61]. Not unexpected, the cetuximab arm had significantly higher rates of grade 3/4 toxicities and adding cetuximab to the cisplatin-RT combination did not improve LRC, PFS, or OS. Studies with anti-EGFR tyrosine kinsase inhibitors such as lapatinib and gefitinib with chemo-radiation were similarly negative, as was a study of the anti-EGFR antibody, panitumumab, plus cisplatin-RT [62-64]. One plausible explanation for these negative trials is that the toxicity burden of radiation-cisplatin is already at the maximum-tolerated level, such that adding EGFR inhibition causes radiotherapy interruption and long term functional deterioration. These compromises in therapy could explain the trend toward a higher LRC rate in the experimental arm. Another potential explanation for lack of benefit is that platinum derivatives and cetuximab have similar mechanisms of radiation sensitization (i.e., inhibition of repair of radiationinduced DNA damage) [65, 66]. In this case, combining cetuximab with agents having different mechanisms of action should be considered. For example, the antitubulin drug docetaxel produced promising results in combination with cetuximab and radiation in a preclinical study [67]. As an illustration of this approach, the RTOG 1216 trial is currently comparing postoperative radiation plus docetaxel and cetuximab versus docetaxel versus cisplatin in high-risk patients. This trial is designed to move into a phase 3 component after an interim analysis is performed with a “pick the winner” between the experimental arms. Can Success be as Simple as Suppressing Inflammation in HNSCC? If combining specific anti-cancer therapies has not improved CRT outcomes, perhaps targeting other pathways may be helpful. One potential avenue is inflammatory modulation through the transforming growth factor β (TGF-β) pathway [68]. TGF-β exerts tumor suppressive effects but can also drive cancers past the carcinogenesis inflexion point via a variety of interactions on the tumor cell and in the surrounding microenvironment. Basically, TGF-β1 signaling occurs principally through a heteromeric complex of type II and type I TGF-β receptors that activates the Smad family pathway. Phosphorylated Smad2 and Smad3, mediated by TβRI, bind to Smad4, and are relocated to the nucleus, resulting in activated TGF-β-driven transcriptional responses [69]. Either as a complementary or alternative mechanism TGF-β signaling also occurs through non-Smad pathways driving cancer cell survival and invasion through epithelial-mesenchymal transformation. Relevant to our field, radiation activates TGF-β signaling pathway with cross-talk activation of COX-2 [70]. Well described are the subsequent increases in serum TGF-β associated with pulmonary injury and fibrosis within normal lung parenchyma [71]. Increases in radiation-produced reactive oxygen species results in immediate activation of latent forms of TGF-β [72]. Marked decreases in radiation induced fibrosis are observed when TGF-β is inhibited. Even a single dose of a TGF-β MAb inhibitor, 1D11, immediately after receiving 5 fractionated doses of radiation in a rodent lung model, significantly 7
reduced inflammation, TGF-β activation and expression, and radiation-induced fibrosis [73]. Similar results were obtained using small molecule inhibitors of TGF-β signaling. Inhibition of the TGF-β pathway enables radiation modulation in various types of cancer cell models [74, 75] and may improve the immune microenvironment through decreasing infiltrating macrophages, downregulation of Treg cells, increasing the amount of CD8+ T-cells, and eliminating expression of distant metastasis [76]. It may be possible to use inhibition of TGF-β dualistically with radiation and additional immune modulating antibodies, leading both to normal tissue protection and tumor radiosensitization. This could be a major successful step toward preventing chronic tissue damage. In an alternative way of looking at this, TGF-β may be both hindering the activation of dendritic cells to present tumor antigens [77] as well as blocking our radiation therapy from inducing an optimal immune environment and creating if you will, an in situ vaccine. Vanpouille et al expands elegantly on the rationale for why blocking TGF-β may restore the needed balance to improve immune response against cancer [78]. Clinical studies combining TGF-β inhibition with radiotherapy will be required to explore the potential clinical utility of such a therapeutic strategy and they are under development. Using Radiation To Start the Fire – Combining With Checkpoint Inhibitors in HNSCC We certainly don’t want to overhype the tidal wave of immunotherapy trials underway and in development, yet a whole different level of understanding about the immune system’s role in preventing and controlling cancers is emerging. A deeper dive has revealed clever ways cancers circumvent or suppress the immune system’s surveillance of non-self antigens. Recent breakthroughs in tumor immunology have opened a glimpse into what may be the new frontier towards durable tumor control for advanced stage cancers including HNSCC. In the metastatic HNSCC setting exciting data are confirming the benefits of using checkpoint inhibitors for patients with chemo-refractory or relapsed cancers [79]. From a radiation oncology perspective, there are many questions about how radiation and immunotherapy will interact. Is it time to redirect our strategy and use radiation as a fire starter for checkpoint inhibitors in HNSCC? What studies can we develop to answer immunotherapy-radiation combinations? Reviewing the entirety of cancer immunology is beyond the scope of this review so the reader is directed toward a comprehensive discussion of cancer inhibitory activity against the immune system [80]. Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), which inhibits initial T-cell activation, and programmed cell death protein 1 (PD-1) which suppresses subsequent T-cell activity in peripheral tissues and tumors have leaped forward in the cancer immune story [81-83]. Attacking these cancer checkpoints not only appear to enhance tumor responses in heavily treated cancers but, in a small percentage of patients, leads to long term immune memory against future cancer regrowth [84]. This is a vastly different concept than applying “targeted agents” against growth factors that so often require continued dosing and added toxicity. Areas desperate for refinement include pre-clinical studies designed to determine the optimal dosing and timing with radiation [85]; whether patients can be selected for these therapies based on molecular studies; how best to combine with complementary immuno-modulatory drugs such as CTLA4 inhibitors; and whether the anti-cancer activity of these agents can be improved with the addition of conventional 8
or a short burst of hypofractionated radiation to stimulate a systemic attack against cancer [86]. Critical to immune mediated therapy in HNSCC may be the presence of tumor-directed CTLs, or lack thereof, as a result of suppressive regulatory T cells and myeloid-derived suppressor cells [86]. The reader is directed to a comprehensive review of immune pathways and targeted biologics in HNSCC related to checkpoint blockades as a reference moving forward [86]. Numerous studies evaluating PD1 inhibition and RT are ongoing (Table 2). Determining how immunotherapy and radiation therapy will interact will be a critical next step in the emerging treatments of HNSCC. Conclusions There have been many recent successes and failures in the combined modality treatment of HNSCC (Figure 1). Technically, radiation oncology treatment planning and delivery has seen monumental advancements and newer approaches such as proton therapy may continue to reduce toxicity in selected settings. Neoadjuvant chemotherapy has largely been a failure, whereas improved radiation techniques have been a success. EGFR inhibition has been a success, but not when combined with chemotherapy. To improve HNSCC care, however, much more needs to be done. The oncology community needs to refine radiation and chemotherapy doses in HPV-positive HNSCC and current clinical trials for these patients will transform how we treat in the future. Clever clinical trial designs are needed to learn how radiation and targeted therapies or immune modulation will interact to maximize survival and minimize toxicity. This may even include hypofractionated radiation rather than traditional 7 week courses to reduced target volumes as our immune system is activated in a positive way. This could finally allow us to move away from the traditional chemo-radiation backbones. Less (but in an elegant way) may be more.
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Table 1. Summary of randomized, phase 3 studies of neoadjuvant chemotherapy followed by definitive therapy. Study
Key inclusion and enrollment numbers
Treatment
Overall survival difference
Toxicity
(HR; 95% CI)
Neoadjuvant chemotherapy prior to surgery for oral cavity cancer Chinese trial
-resectable oral cavity cancers -256 enrolled
TPF followed by surgery and RT vs. surgery and RT alone
None. 0.977; 0.634-1.507, p=0.918
Higher in the TPF arm
Neoadjuvant chemotherapy prior to curative intent concurrent chemoradiation DeCIDE
-T1-T4, N2a-N3 -285 of planned 400 enrolled
TPF followed by DFHX-RT vs. DFHXRT alone
None. 0.91; 0.591.91, p=0.68
-more severe adverse events with neoadjuvant treatment (47% vs 28%, p=0.002) -similar treatment related mortality (3.8% vs 0%, p=0.6)
PARADIGM
-stage III-IVB -145 of planned 300 enrolled
TPF followed by carboplatin or docetaxel-RT vs. cisplatin-RT alone
None. 1.09; 0·59– 2·03, p=0.77
-more febrile neutropenia (21 vs 1%) with neoadjuvant therapy -more grade 3/4 mucositis (47% vs 16%) with neoadjuvant therapy
Spanish Head and
-stage III-IVB
TPF or PF followed by cisplatin-RT vs
None. Log rank
-20% of TPF patients did not 17
Neck Cooperative
GSTTC
-met enrollment goal of 439
cisplatin-RT alone
-stage III-IVB
2x2 design with either PF or TFP followed by PF-RT or cetuximab-RT
-met enrollment goal of 421
0.56
receive CRT -more toxicity in neoadjuvant arms
Present. 0.72; 0.55-0.96, p=0.025
Not yet reported
Abbreviations: HR: Hazard ratio. CI: confidence interval. TFP: cisplatin, docetaxel, and 5-FU. DFHX-RT: docetaxel, 5-FU, hydroxyurea and radiation therapy. PF: cisplatin and 5-FU.
Table 2. Select studies combining immunotherapy and radiation therapy currently enrolling according to clinicaltrials.gov (April 3, 2016). Setting
Therapy
Phase
Registration Number
Curative intent/adjuvant therapy for locally advanced head and neck squamous cell carcinoma Post-operative, adjuvant therapy
Pembrolizumab plus cisplatin-RT
2
NCT02641093
Post-operative, adjuvant therapy
Pembrolizumab plus RT
2
NCT02296684
Curative intent
Pembrolizumab plus RT in cisplatin-ineligible
2
NCT02609503
Curative intent
Pembrolizumab plus cisplatin-RT
2
NCT02586207
Relapsed/metastatic head and neck squamous cell carcinoma R/M HNSCC
Pembrolizumab plus palliative RT
1
NCT02318771
Re-irradiation
Pembrolizumab plus hyperfractionated RT
2
NCT02289209
R/M HNSCC
Nivolumab plus SBRT
2
NCT02684253
Abbreviations: RT: Radiation therapy. R/M: relapsed/metastatic. HNSCC: head and neck squamous cell carcinoma. R/M: relapsed/metastatic. SBRT: stereotactic body radiation therapy. 18
Figure 1. Examples of success and failure in head and neck squamous cell carcinoma therapy
19
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PII: DOI: Reference:
S1053-4296(16)30015-7 http://dx.doi.org/10.1016/j.semradonc.2016.05.004 YSRAO50553
To appear in: Seminars in Radiation Oncology Cite this article as: Daniel W. Bowles, Eric Deutsch and David Raben, Successes and Failures of Combined Modality Therapies in Head and Neck Cancer, Seminars in Radiation Oncology, http://dx.doi.org/10.1016/j.semradonc.2016.05.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Successes and Failures of Combined Modality Therapies in Head and Neck Cancer
1,2
Daniel W. Bowles, M.D., 3Eric Deutsch, M.D., Ph.D., M.D. and 4David Raben, M.D.
1
Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO
2
Department of Medicine, Denver Veterans Affairs Medical Center, Denver, CO
3
Department of Molecular Radiotherapy, Gustave Roussy Cancer Campus, Paris, France.
4
Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO
Address inquiries and reprint requests to: David Raben, MD, Department of Radiation Oncology, University of Colorado Health, Mail Stop F706, 1665 Aurora Court, Suite 1032, Aurora, CO80045. E-mail: [email protected]
ABSTRACT The paradigms for treating head and neck squamous cell carcinoma are changing as new subgroups are defined. The technical successes of improved radiation therapy are many; however, the success of novel combined therapies are few. With the emergence of human papillomavirus (HPV) and the development of immuno-oncology agents, such as checkpoint inhibitors, are we ready to reevaluate how we use radiation and chemotherapy for locally advanced and metastatic disease – will we remain the fire or become the fire starter?
1
Introduction Success or failure in the management of head and neck squamous cell carcinoma (HNSCC) over the past several decades is in the eye of the beholder – as well as in the results of phase 3 trials. After establishing the role of combined cisplatin-based combined chemotherapy and radiation more than three decades ago [1, 2], the acute and long term side effects of curative-intent therapy remain problematic and 5-year overall survival (OS) for non-human papillomavirus (HPV)-driven HNSCC remains poor [3, 4]. New sensitizers, such as the taxanes and/or anti-epidermal growth factor receptor (EGFR) antibodies, are being employed with hopes that they may improve outcomes [5]. Similarly, functional outcomes have improved as radiation techniques have advanced over the past 15 years, yet much more needs to be done. We are now entering a new world with advanced radiation techniques, novel small molecule inhibitors such DNA repair inhibitors, PI3K inhibitors, mTOR inhibitors, and now the burgeoning world of immuno-oncology. Will these new agents and techniques lead to the success we are looking for and will our view of combined modality therapy shift? To help us decide the best way forward in definitive HNSCC management, this review article will review select recent successes and failures in combined modality therapy and provide some thoughts for the future.
It’s Technical: Radiation Success with Improved Planning and Delivery Capabilities Dramatic improvements in radiation software and hardware have enabled radiation oncologists to make the shift from a 3-D to a more elegant intensity modulated radiation therapy (IMRT) world. While not the focus of the review, we would be remiss not to mention how the adoption of IMRT has improved functional outcomes for HNSCC patients. For instance, sparing of the constrictor muscles, mylo/geniohyoid complex and the esophageal inlet, and understanding that reducing the volume of normal tissue exposed to doses greater than 60 Gy reduces long term dysphagia, has been an important achievement [6-8]. We continue to explore a variety of delivery techniques such as volumetricmodulated arc therapy (VMAT) or TOMOtherapy to maximize normal tissue sparing while sending homogenous doses of radiation to the intended targets. Salivary function and quality of life continue to improve as radiation oncologists use parotid and submandibular sparing techniques with no decrease in safety [9-11]. Beyond decreasing long term side effects, IMRT-based approaches may also improve cancer specific survival [12]. Novel radiation techniques may push the envelope further with regards to efficacy and toxicity. For instance, will proton beam radiation therapy take us further down the reduced toxicity pathway? Proton beam radiation therapy reduces acute toxicity compared with IMRT for head and neck tumors that require ipsilateral radiation, but its effect on long term toxicities are unknown [13, 14]. Stereotactic body radiation therapy may allow for more rapid and safe delivery of radiation to he head and neck area similar to what we have achieved in other sites like prostate and pancreas. Time and rigorous comparisons between proton and photon therapy in HNSCC treatment will determine whether protons will be a future success story.
2
The Failure of Neoadjuvant Chemotherapy: Revisiting the Past to see the Future Our goal in this section is not to belabor the failures of neoadjuvant/induction chemotherapy but to drive home the point that this strategy has been investigated extensively in both the organ preservation and pre-operative settings, yet no clear improvements in patient outcomes have been demonstrated. The central theory of neoadjuvant chemotherapy, also referred to as sequential or induction chemotherapy, is that multi-agent chemotherapy given at the beginning of curative-intent therapy can improve OS by improving local-regional control (LRC) and decreasing distant metastatic recurrence. The widespread adoption of neoadjuvant chemotherapy followed by radiation can be traced to the landmark Department of Veterans Affairs Larynx Preservation trial published 25 years ago which demonstrated that neoadjuvant chemotherapy with cisplatin and 5-fluorouracil [FU] (PF) followed by radiation yielded similar survival to laryngectomy followed by radiation in select larynx cancer patients but with improved organ preservation [15]. RTOG 91-11 subsequently demonstrated that concurrent CRT improved organ preservation rates but not OS compared to neoadjuvant chemotherapy followed by RT, however, and concurrent CRT became the standard of care [16]. Introduction of taxanes into the neoadjuvant regimens renewed enthusiasm in the mid-2000’s when TAX323 and TAX324 were published. These two randomized, phase 3 trials demonstrated that the addition of a taxane (docetaxel) to neoadjuvant cisplatin, and 5-FU (TPF) followed by either RT alone or concurrent low dose, weekly carboplatin plus RT yielded superior LRC, progression free survival (PFS), and OS compared to neoadjuvant PF in oropharynx, larynx, and hypopharynx cancers [17, 18]. The GORTEC trial subsequently demonstrated TPF’s superiority over PF followed by RT in larynx cancers and a large meta-analysis confirmed that TPF is a superior neoadjuvant regimen compared to PF [19, 20]. Neoadjuvant chemotherapy before standard of care definitive therapy. Did we achieve any success when we compared the above regimen to CRT or surgery followed by RT? “No” is the unfortunate answer. Several randomized trials have been published comparing neoadjuvant chemotherapy followed by standard of care definitive therapy (Table 1). A study from China administered TPF prior to surgical resection for oral cavity SCC versus surgery upfront and found that, while a complete response to TPF predicted improved OS, there was no OS difference between the entire TPF and non-TPF groups [21]. Two United States-based phase 3 trials, DeCIDE and PARADIGM, failed to demonstrate a clear benefit to neoadjuvant chemotherapy compared to concurrent CRT (Table 1) [22, 23]. Both of these studies randomized patients to CRT or CRT preceded by neoadjuvant TPF. In both studies there was no difference in OS between the two groups (hazard ratio [HR] 0.91; 95% confidence interval [CI] 0.59-1.91; p=0.68 in the DeCIDE trial; HR 1.09; 95% CI 0·59–2·03; p=0.77 in the PARADIGM trial) and no specific subgroup has experienced an OS benefit from neoadjuvant TPF. Adding to the lack of survival success was consistently higher toxicity in the neoadjuvant arms. A phase 3 study from Spain with a similar treatment plan to PARADIGM also failed to demonstrate an improvement in OS with neoadjuvant chemotherapy at the cost of excess toxicity (Table 1). While these studies lacked the statistical power to demonstrate improved OS due to poor accrual and/or longer than expected 3
survival in the control group, the results were disappointing and point to neoadjuvant chemotherapy’s shortcomings [24]. Are there any neoadjuvant success stories? The only randomized study to report an OS advantage to neoadjuvant chemotherapy was an ambitious 2x2 trial from Italy [25]. Patients were randomized to four arms: 1) concurrent PF and standard fraction RT; 2) cetuximab and concurrent RT; 3) TPF x 3 cycles followed by concurrent PF-RT; 4) TPF followed by cetuximab-RT. For the initial analysis, the two neoadjuvant arms were combined and compared to the two concurrent CRT arms, demonstrating an improvement in 3-year PFS (HR 0.73; 95%CI 0.57-0.94, p=0.015) and OS (HR 0.72; 95%CI 0.55-0.96; p=0.025) for neoadjuvant chemotherapy. A subgroup analysis suggested TPF followed by cetuximab-RT may be superior to the other regimens (HR 0.57; 95% CI 0.34-0.93); however, the power to make this conclusion was limited. Toxicity did not differ significantly between all 4 arms. While the results of this study are provocative, it should be noted that this has only been presented in abstract form. The French GORTEC trials (NCT01233843) will address this topic further; however, at this point neoadjuvant chemotherapy should not be routinely given for patients with locally advanced HNSCC.
Accelerated Chemo-Radiation Therapy: A Bridge to Far? There was excitement that accelerated radiation (RTOG 9003) combined with concurrent chemotherapy would improve LRC and OS. The phase 3 RTOG 0129 and the GORTEC 99-02 studies attempted to answer this question, comparing conventional cisplatin-RT to accelerated cisplatin-radiation (or accelerated radiation alone in GORTEC). Unfortunately, neither trial demonstrated any improvements in LRC, PFS, or OS [26, 27]. As a result, new studies looking at accelerated CRT are limited. Let us emphasize to our readers that accelerated radiation and hyperfractionated radiation are different strategies with different toxicities and biological effects as RTOG 9003 enlightened us. The latter approach is generally offered at a dose per fraction of 1.1-1.2 Gy twice daily to doses ranging from ~74.4 Gy to 81.6 Gy. Thus it does provide ~6-12% dose escalation benefit. One could argue that we have never really done a study of hyperfractionated CRT to conventional CRT. Speculation here but our sense is that this might provide incremental benefits but at what cost? Success in Radiation Dose De-escalation? Induction chemotherapy and accelerated CRT have not been highly successful as therapeutic intensification strategies in HNSCC. Perhaps as a result, many studies are now heading in the opposite direction, trying to find ways to safely de-escalate therapy in patients with favorable prognoses. Numerous studies have clearly demonstrated improved OS for patients in HPV-related HNSCC [28, 29]. A study from the University of North Carolina recently demonstrated excellent local control in HPVpositive patients using reduced doses of radiation (60 Gy) and cisplatin (30mg/m2 weekly) [30]. ECOG 1308 assigned patients to neoadjuvant cisplatin, paclitaxel, and cetuximab with hopes of reducing 4
macroscopic tumor volume. Patients with a complete response (CR) were treated with de-escalated radiation (54 Gy), whereas others received standard dose radiation (66-70 Gy). In patients obtaining a CR (71% of patients) followed by reduced RT, a 2-year PFS of 80% and 2-year OS of 93% was observed, compared to 65% and 87% in the non-CR group, respectively [31]. These hypothesis generating data suggest that there may be role for neoadjuvant chemotherapy to determine the feasibility of a reduced radiation dose. Investigators at Mr. Sinai are leading a randomized, phase 3 “Quarterback” trial (NCT01706939) in which patients who have a clinical or radiographic partial or complete response to three cycles of TPF are randomized to carboplatin plus low-dose (56 Gy) or standard dose (70 Gy) radiation. Success here will be an opportunity to move away from a “one size fits all” approach and dramatically reduce radiation dose in a select group of patients that respond well to neoadjuvant chemotherapy. Complete elimination of chemotherapy may be the next step for select HPV-positive oropharyngeal patients based on emerging single institution data [32]. The NRG has subsequently embarked on an ambitious study (HN002) to evaluate good prognosis oropharyngeal cancer patients with reduced dose radiation (60 Gy) alone versus reduced dose radiation (60 Gy) with weekly cisplatin (NCT02254278). Success in management of this distinct biologic entity will rest on additional understanding of the differences between HPV positive and negative disease as it relates to driver mutations, inflammatory or non-inflammatory phenotypes and prognostics biomarkers in the genomic arena [33]. Where Do We Stand With Radiation Modulators? Modifying radiation delivery and dose may be important ways to improve HNSCC therapy; however, improvements in sensitizing agents may also improve outcomes. Drugs that affect radiosensitivity by targeting key cell survival pathways are likely to affect both tumors and normal tissues. Therefore, the balance between the tumor versus normal tissue differential response to radiotherapy of any novel drug radiation combination must be considered in treatment development. To date, one of the main factors limiting the implementation of radiosensitizers and radioprotectors in clinical care has been the nonspecific mechanism of action of these agents. Improved understanding of the optimal way to combine radiosensitizers in the context of clinical realities is needed to selectively increase tumor cell killing and local control while minimally affecting normal tissues. Targeting signal transduction pathways – any successes? The identification of critical survival pathways that influence cell fate after irradiation has contributed to render molecular-targeted therapies an attractive approach to maximize the therapeutic ratio of radiotherapy. Several survival pathways are activated following ionizing radiation, including PI3K, mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), Hedgehog, and transforming growth factor-β (TGFβ) pathways [34-36]. In addition to regulating cell death, these pathways can affect the tumor microenvironment and sometimes activate DNA damage repair [37, 38] [39]. As a result, inhibition of these pathways has the potential to increase the response to ionizing radiation of cancer cells through multiple mechanisms. 5
Blocking alternative or complementary pathways to EGFR – PI3K-AKT and mTOR The PI3K–AKT pathway is activated by various mutations that are commonly found in cancer, including receptor tyrosine kinase activations, activating mutations in PI3K, loss of the tumor suppressor phosphatase and tensin homolog (PTEN) [40]. Importantly, and similar to EGFR, activation of the PI3K– AKT pathway contributes to radiation resistance. As a result, selective inhibitors of this pathway increase the radiosensitivity of cancer cells, and many drugs targeting this pathway are currently in preclinical development or in clinical trials [41]. The specific activating mutations in tumors must be considered when targeting the PI3K–AKT signaling pathway, as drugs that block signaling upstream of the mutant protein may not be effective. Downstream blockade of the PI3K pathway using mTOR inhibitors combined with radiotherapy has yielded controversial results in terms of safety in phase 1/2 series in lung [42] or HNSCC tumors [43], underscoring the need for further optimization. The clinical relevance of PI3K mutations and its relationship to HPV positive head and neck cancers remains to be determined [44]. Lest we get too excited, recent randomized phase 2 trials comparing PX-866, an irreversible PI3K inhibitor, plus docetaxel or cetuximab versus docetaxel or cetuximab failed to demonstrate any survival or response benefits in both HPV-positive and HPV-negative patients [45, 46].
EGFR inhibition – lessons learned In order to find success, perhaps we need to reflect critically on the disconnect between our “promising” pre-clinical studies and failed clinical trials with biologic modulators lumped in with cisplatin-radiation [47]. It has been a long and winding road of failed trials with EGFR inhibitors and CRT. As a brief background, EGFR is a tyrosine kinase that signals through RAS and PI3K pathways. EGFR is commonly overexpressed in HNSCC [48-50]. High EGFR expression is associated with poor response to radiation [49] or chemoradiotherapy [50] while EGFR inhibitors have been shown to sensitize tumors to cisplatin [51] or radiation.[52-54] . Like a broken record we talk about the only trial with a biologic agent to improve outcomes with radiation but it is all we have to date. Importantly, and with fortuitous hindsight, no chemotherapy was administered giving our field the opportunity to study in a pure sense, anti-EGFR therapy with radiation. This seminal phase 3 study of the anti-EGFR antibody, cetuximab, and radiation demonstrated durable improvements in OS compared to radiation alone [55]. However, digging deeper into this study one must consider the results in the setting of p16 (HPV) status. Cetuximab appeared to demonstrate a OS and LRC benefit irrespective of p16 status in patients with oropharyngeal cancer over radiotherapy alone, though the number of p16-positive patients was small [56]. In this trial, with the exception of EGFR inhibition-caused acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the control and the study arms. In sharp contrast, some cases of major toxicities encountered in HNSCC patients treated with radiotherapy and cetuximab have since been described and a recent study suggests the overall toxicity between cisplatin6
RT and cetuximab-RT are similar [57-59]. EGFR polymorphisms may correlate with major toxicities in cetuximab-RT [60], but this still remains controversial and does not constitute part of the routine pretherapeutic assessment of patients receiving cetuximab based CRT. We next followed the yellow brick road given cetuximab’s success as a radiation sensitizer, and “logically” compared cisplatin-RT to cetuximab plus cisplatin-RT in RTOG 0522. [61]. Not unexpected, the cetuximab arm had significantly higher rates of grade 3/4 toxicities and adding cetuximab to the cisplatin-RT combination did not improve LRC, PFS, or OS. Studies with anti-EGFR tyrosine kinsase inhibitors such as lapatinib and gefitinib with chemo-radiation were similarly negative, as was a study of the anti-EGFR antibody, panitumumab, plus cisplatin-RT [62-64]. One plausible explanation for these negative trials is that the toxicity burden of radiation-cisplatin is already at the maximum-tolerated level, such that adding EGFR inhibition causes radiotherapy interruption and long term functional deterioration. These compromises in therapy could explain the trend toward a higher LRC rate in the experimental arm. Another potential explanation for lack of benefit is that platinum derivatives and cetuximab have similar mechanisms of radiation sensitization (i.e., inhibition of repair of radiationinduced DNA damage) [65, 66]. In this case, combining cetuximab with agents having different mechanisms of action should be considered. For example, the antitubulin drug docetaxel produced promising results in combination with cetuximab and radiation in a preclinical study [67]. As an illustration of this approach, the RTOG 1216 trial is currently comparing postoperative radiation plus docetaxel and cetuximab versus docetaxel versus cisplatin in high-risk patients. This trial is designed to move into a phase 3 component after an interim analysis is performed with a “pick the winner” between the experimental arms. Can Success be as Simple as Suppressing Inflammation in HNSCC? If combining specific anti-cancer therapies has not improved CRT outcomes, perhaps targeting other pathways may be helpful. One potential avenue is inflammatory modulation through the transforming growth factor β (TGF-β) pathway [68]. TGF-β exerts tumor suppressive effects but can also drive cancers past the carcinogenesis inflexion point via a variety of interactions on the tumor cell and in the surrounding microenvironment. Basically, TGF-β1 signaling occurs principally through a heteromeric complex of type II and type I TGF-β receptors that activates the Smad family pathway. Phosphorylated Smad2 and Smad3, mediated by TβRI, bind to Smad4, and are relocated to the nucleus, resulting in activated TGF-β-driven transcriptional responses [69]. Either as a complementary or alternative mechanism TGF-β signaling also occurs through non-Smad pathways driving cancer cell survival and invasion through epithelial-mesenchymal transformation. Relevant to our field, radiation activates TGF-β signaling pathway with cross-talk activation of COX-2 [70]. Well described are the subsequent increases in serum TGF-β associated with pulmonary injury and fibrosis within normal lung parenchyma [71]. Increases in radiation-produced reactive oxygen species results in immediate activation of latent forms of TGF-β [72]. Marked decreases in radiation induced fibrosis are observed when TGF-β is inhibited. Even a single dose of a TGF-β MAb inhibitor, 1D11, immediately after receiving 5 fractionated doses of radiation in a rodent lung model, significantly 7
reduced inflammation, TGF-β activation and expression, and radiation-induced fibrosis [73]. Similar results were obtained using small molecule inhibitors of TGF-β signaling. Inhibition of the TGF-β pathway enables radiation modulation in various types of cancer cell models [74, 75] and may improve the immune microenvironment through decreasing infiltrating macrophages, downregulation of Treg cells, increasing the amount of CD8+ T-cells, and eliminating expression of distant metastasis [76]. It may be possible to use inhibition of TGF-β dualistically with radiation and additional immune modulating antibodies, leading both to normal tissue protection and tumor radiosensitization. This could be a major successful step toward preventing chronic tissue damage. In an alternative way of looking at this, TGF-β may be both hindering the activation of dendritic cells to present tumor antigens [77] as well as blocking our radiation therapy from inducing an optimal immune environment and creating if you will, an in situ vaccine. Vanpouille et al expands elegantly on the rationale for why blocking TGF-β may restore the needed balance to improve immune response against cancer [78]. Clinical studies combining TGF-β inhibition with radiotherapy will be required to explore the potential clinical utility of such a therapeutic strategy and they are under development. Using Radiation To Start the Fire – Combining With Checkpoint Inhibitors in HNSCC We certainly don’t want to overhype the tidal wave of immunotherapy trials underway and in development, yet a whole different level of understanding about the immune system’s role in preventing and controlling cancers is emerging. A deeper dive has revealed clever ways cancers circumvent or suppress the immune system’s surveillance of non-self antigens. Recent breakthroughs in tumor immunology have opened a glimpse into what may be the new frontier towards durable tumor control for advanced stage cancers including HNSCC. In the metastatic HNSCC setting exciting data are confirming the benefits of using checkpoint inhibitors for patients with chemo-refractory or relapsed cancers [79]. From a radiation oncology perspective, there are many questions about how radiation and immunotherapy will interact. Is it time to redirect our strategy and use radiation as a fire starter for checkpoint inhibitors in HNSCC? What studies can we develop to answer immunotherapy-radiation combinations? Reviewing the entirety of cancer immunology is beyond the scope of this review so the reader is directed toward a comprehensive discussion of cancer inhibitory activity against the immune system [80]. Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), which inhibits initial T-cell activation, and programmed cell death protein 1 (PD-1) which suppresses subsequent T-cell activity in peripheral tissues and tumors have leaped forward in the cancer immune story [81-83]. Attacking these cancer checkpoints not only appear to enhance tumor responses in heavily treated cancers but, in a small percentage of patients, leads to long term immune memory against future cancer regrowth [84]. This is a vastly different concept than applying “targeted agents” against growth factors that so often require continued dosing and added toxicity. Areas desperate for refinement include pre-clinical studies designed to determine the optimal dosing and timing with radiation [85]; whether patients can be selected for these therapies based on molecular studies; how best to combine with complementary immuno-modulatory drugs such as CTLA4 inhibitors; and whether the anti-cancer activity of these agents can be improved with the addition of conventional 8
or a short burst of hypofractionated radiation to stimulate a systemic attack against cancer [86]. Critical to immune mediated therapy in HNSCC may be the presence of tumor-directed CTLs, or lack thereof, as a result of suppressive regulatory T cells and myeloid-derived suppressor cells [86]. The reader is directed to a comprehensive review of immune pathways and targeted biologics in HNSCC related to checkpoint blockades as a reference moving forward [86]. Numerous studies evaluating PD1 inhibition and RT are ongoing (Table 2). Determining how immunotherapy and radiation therapy will interact will be a critical next step in the emerging treatments of HNSCC. Conclusions There have been many recent successes and failures in the combined modality treatment of HNSCC (Figure 1). Technically, radiation oncology treatment planning and delivery has seen monumental advancements and newer approaches such as proton therapy may continue to reduce toxicity in selected settings. Neoadjuvant chemotherapy has largely been a failure, whereas improved radiation techniques have been a success. EGFR inhibition has been a success, but not when combined with chemotherapy. To improve HNSCC care, however, much more needs to be done. The oncology community needs to refine radiation and chemotherapy doses in HPV-positive HNSCC and current clinical trials for these patients will transform how we treat in the future. Clever clinical trial designs are needed to learn how radiation and targeted therapies or immune modulation will interact to maximize survival and minimize toxicity. This may even include hypofractionated radiation rather than traditional 7 week courses to reduced target volumes as our immune system is activated in a positive way. This could finally allow us to move away from the traditional chemo-radiation backbones. Less (but in an elegant way) may be more.
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Table 1. Summary of randomized, phase 3 studies of neoadjuvant chemotherapy followed by definitive therapy. Study
Key inclusion and enrollment numbers
Treatment
Overall survival difference
Toxicity
(HR; 95% CI)
Neoadjuvant chemotherapy prior to surgery for oral cavity cancer Chinese trial
-resectable oral cavity cancers -256 enrolled
TPF followed by surgery and RT vs. surgery and RT alone
None. 0.977; 0.634-1.507, p=0.918
Higher in the TPF arm
Neoadjuvant chemotherapy prior to curative intent concurrent chemoradiation DeCIDE
-T1-T4, N2a-N3 -285 of planned 400 enrolled
TPF followed by DFHX-RT vs. DFHXRT alone
None. 0.91; 0.591.91, p=0.68
-more severe adverse events with neoadjuvant treatment (47% vs 28%, p=0.002) -similar treatment related mortality (3.8% vs 0%, p=0.6)
PARADIGM
-stage III-IVB -145 of planned 300 enrolled
TPF followed by carboplatin or docetaxel-RT vs. cisplatin-RT alone
None. 1.09; 0·59– 2·03, p=0.77
-more febrile neutropenia (21 vs 1%) with neoadjuvant therapy -more grade 3/4 mucositis (47% vs 16%) with neoadjuvant therapy
Spanish Head and
-stage III-IVB
TPF or PF followed by cisplatin-RT vs
None. Log rank
-20% of TPF patients did not 17
Neck Cooperative
GSTTC
-met enrollment goal of 439
cisplatin-RT alone
-stage III-IVB
2x2 design with either PF or TFP followed by PF-RT or cetuximab-RT
-met enrollment goal of 421
0.56
receive CRT -more toxicity in neoadjuvant arms
Present. 0.72; 0.55-0.96, p=0.025
Not yet reported
Abbreviations: HR: Hazard ratio. CI: confidence interval. TFP: cisplatin, docetaxel, and 5-FU. DFHX-RT: docetaxel, 5-FU, hydroxyurea and radiation therapy. PF: cisplatin and 5-FU.
Table 2. Select studies combining immunotherapy and radiation therapy currently enrolling according to clinicaltrials.gov (April 3, 2016). Setting
Therapy
Phase
Registration Number
Curative intent/adjuvant therapy for locally advanced head and neck squamous cell carcinoma Post-operative, adjuvant therapy
Pembrolizumab plus cisplatin-RT
2
NCT02641093
Post-operative, adjuvant therapy
Pembrolizumab plus RT
2
NCT02296684
Curative intent
Pembrolizumab plus RT in cisplatin-ineligible
2
NCT02609503
Curative intent
Pembrolizumab plus cisplatin-RT
2
NCT02586207
Relapsed/metastatic head and neck squamous cell carcinoma R/M HNSCC
Pembrolizumab plus palliative RT
1
NCT02318771
Re-irradiation
Pembrolizumab plus hyperfractionated RT
2
NCT02289209
R/M HNSCC
Nivolumab plus SBRT
2
NCT02684253
Abbreviations: RT: Radiation therapy. R/M: relapsed/metastatic. HNSCC: head and neck squamous cell carcinoma. R/M: relapsed/metastatic. SBRT: stereotactic body radiation therapy. 18
Figure 1. Examples of success and failure in head and neck squamous cell carcinoma therapy
19