526685
research-article2014
AORXXX10.1177/0003489414526685Annals of Otology, Rhinology & LaryngologyFlavill et al
Article
Induction Chemotherapy Followed by Concurrent Chemoradiotherapy for Advanced Stage Oropharyngeal Squamous Cell Carcinoma With HPV and P16 Testing
Annals of Otology, Rhinology & Laryngology 2014, Vol. 123(5) 365–373 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003489414526685 aor.sagepub.com
Eric Flavill, MD1, Yisheng V. Fang, MD, PhD2, Brett Miles, DDS, MD1,3, John Truelson, MD1, and Steve Perkins, MD4
Abstract Objective: The objective was to report our experience with advanced stage oropharyngeal squamous cell carcinoma treated sequentially with induction chemotherapy followed by concurrent chemoradiotherapy. Methods: Retrospective chart review identified 49 eligible patients with advanced stage oropharyngeal squamous cell carcinoma treated with induction chemotherapy followed by concurrent chemoradiotherapy. HPV and p16INK4A testing was performed on pathology specimens. Follow-up of over 11 months was required unless a death or treatment failure occurred before that time. Results: Treatment with induction chemotherapy followed by concurrent chemoradiotherapy resulted in 44/48 (90%) complete durable response. One death occurred from pulmonary embolism. Toxicity profiles were comparable to other published data. Average follow-up was 3.9 years. Oncologic failure rates among subgroups showed 5.7% failure for HPV+/ p16+ cancer, 9.1% failure for HPV-/p16+ cancer, 100% failure for HPV-/p16- cancer, 0% failure for nonsmokers, and 17.9% failure for smokers. Conclusions: This study showed favorable outcomes in terms of durable oncologic response and acceptable toxicity profiles. It is notable that 36/49 patients were HPV+/p16+ and 11/49 were HPV-/p16+. Only 2 patients were HPV-/p16-, and both died as a result of oncologic failures. This highlights the importance of obtaining HPV and p16 testing in studies evaluating the efficacy of treatments for oropharyngeal squamous cell carcinoma. Keywords oropharyngeal squamous cell carcinoma, induction chemotherapy, sequential chemotherapy, human papilloma virus, p16 Although concurrent chemoradiotherapy (CCRT) is widely accepted treatment for advanced stage oropharyngeal squamous cell carcinoma (opSCCA), induction chemotherapy (IC) remains controversial. ROTG 91-11 demonstrated IC followed by radiotherapy produced inferior local control for laryngeal cancer compared to CCRT.1 Based on ROTG 91-11 and other studies, CCRT became the nonsurgical treatment of choice for advanced head and neck cancer.2 Subsequently, 2 large studies (TAX 323 and TAX 324) demonstrated positive outcomes using an IC regime that included a taxane.3,4 TAX 324 specifically evaluated IC followed by CCRT (IC-CRT).4 IC-CRT has since gained additional attention as a treatment modality for these patients. At the same time, the prognostic importance of human papilloma virus (HPV) and p16INK4A status for the oropharyngeal subsite has become well recognized.4-6 Because of the significant impact of HPV and p16INK4A status, it is possible
that studies regarding the efficacy of any given treatment modality for opSCCA could be significantly skewed by these factors. This retrospective chart review reports our experience with advanced opSCCA treated with IC-CRT. Disease free survival, side effect/toxicity profiles, and HPV/ p16INK4A status are reported. 1
Department of Otolaryngology/Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA 2 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA 3 Mount Sinai Hospital, New York, New York, USA 4 Hematology/Oncology, Baylor Medical Center, Dallas, Texas, USA Corresponding Author: Eric Flavill, MD, Department of Otolaryngology/Head and Neck Surgery, University of Texas Southwestern Medical Center, PO Box 72, Wilmington, OH 45177, USA. Email: [email protected]
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Materials and Methods
Table 1. Patient Clinical Characteristics (49 Patients Evaluated).
This is a retrospective review of patients diagnosed with advanced stage opSCCA who received primary IC-CRT. Approval was obtained from the UT Southwestern Medical Center institutional review board. Inclusion criteria were as follows: (1) diagnosis of stage III or IV opSCCA between January 1, 2003, and June 1, 2009, (2) no history of prior chemotherapy or radiotherapy, (3) no prior surgical treatment of the cancer, (4) pathology specimen for HPV and p16INK4A testing, (5) no definitive distant metastases at initiation of treatment, (6) adequate follow-up records, and (7) IC-CRT with curative intent. Patients were required to have over 11 months follow-up. If treatment failure or death occurred, the patient was included in the study regardless of follow-up. Patients were excluded if they were under 18 years old, pregnant, or mentally handicapped. A database of patients receiving CCRT was used to identify 246 potentially suitable patient records. These charts provided 49 patients that satisfied inclusion criteria. Study patients were randomly assigned a reference code from A01 to A49 to allow for clear description of treatment failures in the results and discussion sections. Pathology specimens were reviewed to confirm diagnosis and adequacy of the available specimen. HPV testing was then performed using the family 16 in-situ hybridization probe (F16) which detects HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 66. We utilized the INFORM HPV III Family 16 Probe (B) by Ventana Medical Systems, Inc (Tucson, Arizona, USA). Qualitative p16INK4A immunohistochemical testing was performed with CINtec Histology V-Kit from mtm laboratories, Inc (Westborough, Massachusetts, USA). The IC used consisted of paclitaxel-carboplatin, paclitaxel-carboplatin-cetuximab, or docetaxel-cisplatin-fluorouracil (TPF). Thirty patients received 6 courses of paclitaxel-carboplatin. These medications were given weekly for 6 weeks. Due to treatment complications some patients received only 5, 4, or 3 weekly doses of induction paclitaxel-carboplatin. One patient received a single dose of TPF then 4 doses of paclitaxel-carboplatin. Another patient received TPF for 3 weekly doses. The remaining patients received 4-6 doses of paclitaxel-carboplatin with 1-6 associated cetuximab doses. Patients received filgrastim 4-5 days after each dose of IC. They were given premedication with diphenhydramine, ondansetron, ranitidine, and dexamethasone prior to IC doses. Patients were started on CCRT approximately 2 weeks after completing IC. CCRT treatments included cisplatinfluorouracil, cisplatin alone, carboplatin alone, cisplatinfluorouracil followed by carboplatin-fluorouracil, and cisplatin followed by carboplatin. The radiation component consisted of intensity modulated radiotherapy (IMRT). Patients received 60-72 Gy to the primary site and 50-55 Gy
Patient Clinical Characteristics Age at diagnosis, y Mean Median Range Sex Male Female Smoking history No Yes Mean, pack-yearsa Median, pack-yearsa Range, pack-yearsa Ethanol use None Occasional/mild Moderate/heavy Medical comorbidity present at diagnosis Hypertension Diabetes Coronary artery disease ECOG performance status at diagnosis 0, asymptomatic 1, symptomatic, fully ambulatory 2, symptomatic, in bed < 50% of the day 3, symptomatic, in bed > 50% of the day but not bedridden 4, bedridden 5, dead
No. (%) 55.43 53.94 35.71-77.74 45 (92) 4 (8) 21 (43) 28 (57) 37.5 35 2-105 14 (28) 23 (47) 12 (25) 16 (33) 4 (8) 6 (12) 38 (78) 8 (16) 2 (4) 1 (2) 0 (0) 0 (0)
a
Patient A08 used cigars and pipe and so is counted as a smoker, but pack-year history data are not available, so he is not included in mean, median, and range data for pack-years.
to the neck. Radiation fractions ranged from 30 to 34 fractions over 38 to 49 days.
Results A total of 49 patients met inclusion criteria and had sufficient pathology specimens for HPV and p16INK4A testing. One patient (A40) died 5 days after completing CCRT. He is excluded from oncologic outcome data but is included in patient demographic and initial IC data. This left 48 patients for late toxicity and long-term oncologic outcome data. Table 1 shows patient demographics and comorbidities. Patients are divided into 3 groups by HPV and p16INK4A status: (1) HPV positive/p16 positive (HPV+/p16+), (2) HPV negative/p16 positive (HPV-/p16+), (3) HPV negative/p16 negative (HPV-/p16-). HPV/p16 data are reported in Table 2. Notably, there were only 2 patients (4%) in the HPV-/ p16- group. No patients were HPV positive and p16INK4A
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Flavill et al Table 2. Patient Pathologic Characteristics for Oncologic Outcome Group (48 Patients Evaluated).a Patient Pathological Characteristics
No. (%)
HPV positive HPV negative P16 positive P16 negative Smoking history No Yes HPV positive/p16 positive HPV negative/p16 positive HPV negative/p16 negative
35 (73) 13 (27) 46 (96) 2 (4) 20 (42) 28 (58) 35 (73) 11 (23) 2 (4)
a Patient A40 excluded due to death 5 days post-CCRT (he was HPV+/ p16+ and a nonsmoker).
Table 4. Toxicity of Induction Regimen (49 Patients Evaluated). Neuropathy from Induction Chemotherapy
No. (%)
0 = None 1 = Paresthesias and/or decreased deep tendon reflexes 2 = Severe paresthesias and/or mild weakness 3 = Intolerable paresthesias and/or motor loss 4 = Paralysis Infection/thrombosis from induction chemotherapy 0 = None 1 = Sepsis 2 = Mediport infection 3 = Phlebitis, local cellulitis 4 = Deep venous thrombosis
26 (53) 9 (18) 13(27) 1 (2) 42 (86) 2 (4) 2 (4) 1 (2) 4 (8)
Table 3. Staging (49 Patients Evaluated). Primary Tumor Site and Staging Site of primary tumor Tonsil Base of tongue Oropharynx Stage of primary tumor T1 T2 T3 T4 Nodal stage N0 N1 N2a N2b N2c N3 Overall stage of disease I II III IV
No. (%) 21 (43) 26 (53) 2 (4) 3 (6) 16 (33) 21 (43) 9 (18) 4 (8) 8 (16) 2 (4) 20 (41) 12 (25) 3 (6) 0 (0) 0 (0) 10 (0) 39 (80)
negative. Tumor site and staging are shown in Table 3. Two patients were labeled oropharynx because the subsite could not be distinguished.
Toxicity and Side Effects Table 4 shows documented toxicity during and immediately after IC. Table 5 reports toxicity during or shortly after CCRT. One patient (A40) died of a pulmonary embolism from a deep venous thrombosis 5 days after completing CCRT. Symptomatic mucositis was present in all but 1
Table 5. Toxicity of Concurrent Chemoradiotherapy Regimen (49 Patients Evaluated). Neuropathy
No. (%)
0 = None 1 = Paresthesias and/or decreased deep tendon reflexes 2 = Severe paresthesias and/or mild weakness 3 = Intolerable paresthesias and/or motor loss 4 = Paralysis Infection/thrombosis 0 = None 1 = Sepsis 2 = Mediport infection 3 = Phlebitis, local cellulitis 4 = Deep venous thrombosis 5 = Deep venous thrombosis/pulmonary embolism Mucositis 0 = None 1 = Erythema/soreness 2 = Ulcers/erythema ability to eat solids 3 = Ulcers, required liquid diet 4 = Unable to maintain nutrition PO Nutritional status during therapy 0 = Oral adequate 1 = PEG 2 = TPN 3 = TPN/PEG
33 (68) 5 (10) 9 (18) 2 (4) 0 (0) 27 (55) 4 (8) 9 (18) 2 (4) 13 (27) 4 (8)
1 (2) 2 (4) 2 (4) 17 (35) 27 (55) 16 (33) 15 (31) 14 (28) 4 (8)
Abbreviations: PEG, percutaneous endoscopic gastrostomy; PO, per ss; TPN, total parenteral nutrition.
patient during CCRT. Fourteen patients required total parenteral nutrition (TPN) during CCRT and 4 of them also
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Table 6. Posttreatment Toxicity Profile at Last Follow-Up (49 Patients Evaluated).a Dysphagia
No. (%)
33 (68) 6 (12) 6 (12) 1 (2) 1 (2) 2 (4)
0 = All foods without difficulty 1 = Solid foods with some difficulty 2 = Soft or semisolid foods only 3 = Liquids only 4 = No foods/saliva N/A = Patient expired before long-term outcome data could be established Xerostomia 0 = None/mild 1 = Clinically significant/symptomatic N/A = Patient expired before long-term outcome data could be established Taste disturbance 0 = None/mild 1 = Yes/significant N/A = Patient expired before long-term outcome data could be established Osteoradionecrosis 0 = None 1 = Yes N/A = Patient expired before long-term outcome data could be established
7 (14) 40 (82) 2 (4)
37 (76) 10 (20) 2 (4)
46 (94) 1 (2) 2 (4)
a Toxicity profile present at last follow-up was available for 47 patients with a range of 8 to 95 months after completing induction chemotherapy followed by concurrent chemoradiotherapy. Patients A40 and A18 both died before posttreatment toxicity data could be obtained and are recorded in the table under N/A.
received gastrostomy tube. TPN was attempted to avoid gastrostomy tube or to provide nutrition while awaiting gastrostomy tube placement. The side effect profile available at last follow-up is shown in Table 6. Thirty-three of the 47 patients with available data were able to eat all foods without difficulty at their last clinical follow-up. Twelve of the remaining patients were either taking solids with some difficulty or eating soft foods. Only 1 patient was unable to take anything by mouth. Taste disturbance was also limited in this study population. Thirty-seven of the 47 patients had either no taste disturbance or only mild disturbance. Xerostomia was prevalent, however, with 40 of the 47 patients experiencing clinically significant dry mouth symptoms.
Initial Clinical Response to Induction and Correlation With Long-Term Outcome Clinical assessment of response to treatment was performed at the completion of induction therapy. CT scans were not
routinely employed for this purpose, so these data are primarily derived from physical examination and flexible laryngoscopy. The results are shown in Table 7. A complete clinical response to IC occurred in 38/49 patients. The patient who died of a pulmonary embolism 5 days after completing CCRT was in this group (A40), leaving 37 patients. Of these 37 patients, 35 went on to have durable complete responses. Nine patients had only a partial clinical response to IC. Seven of these partial responders had a complete durable response after CCRT and were free of oncologic disease at last follow-up. Only 2 patients had no response to IC. One of these patients had a durable complete response after CCRT. The other had an initial complete response to CCRT but subsequently failed at both primary and distant (lung) sites. He ultimately died of sequelae from his opSCCA.
Overall Response and Discussion of Treatment Failures Of the 49 patients in this study, 1 died of a pulmonary embolism 5 days after completing CCRT (A40). This patient had an apparent complete response to treatment. He is excluded from oncologic outcome data as it cannot be determined if this response would have been durable. Fortythree of the remaining 48 patients (89.6%) had durable complete responses documented after IC-CRT. All were alive and disease-free as of our most current follow-up data. Average follow-up for these patients was 46.8 months (3.9 years) with a median of 42.6 months. Five patients (5/48 = 10.4%) had oncologic failures with recurrent/residual disease identified (patients A9, A18, A20, A27, and A41). One of these patients had evidence of treatment failure within the first 1.5 months post-CCRT. The other 4 patients were identified to have oncologic failure between 5.3 and 15.1 months post-CCRT. The sites of oncologic failure were 3/48 (6.25%) at primary site, 2/48 (4.17%) at the neck, and 3/48 (6.25%) at distant sites. Three of the patients failed at multiple sites (A9, A18, A20) and 2 patients failed at only 1 site (A27, A41). One of the oncologic failures was lost to follow-up (A41). The other 4 were followed until their deaths. For these 4 patients, the survival ranged from 4.3 to 31.47 months post-CCRT with an average survival of 16.62 months post-CCRT. Treatment failures are shown in Table 8. Patients with a smoking history had an oncologic failure rate of 5/28 (17.9%). The 20 lifelong nonsmokers were all free of oncologic disease at their last follow-up. Note that patient A40 is excluded from the oncologic outcome data for the nonsmoking group due to his death 5 days after completing CCRT. Among patients that had HPV+/p16+ cancer, 2/35 (5.7%) showed evidence of oncologic failure. One patient (A41) failed at the neck and the other (A18) failed at the
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Flavill et al Table 7. Initial Clinical Response to Induction Chemotherapy—Correlation to Final Outcomes.
Early PostComplete All Durable CCRT Failure,b Outcomes Cure Any Site Response to IC After CCRT All groups Complete response (NED) Partial response No reduction in tumor
Early PostCCRT Failure Early PostCCRT Failure at Neck Lymph Nodes at Primary Site
Early PostCCRT Failure at Distant Site
Post-CCRT Complete Response Followed by Failure,c Any Site
Post-CCRT Complete Response Followed by Failure at Primary Site
Post-CCRT Complete Post-CCRT Response Complete Followed by Response Failure at Followed by Failure at Neck Distant Site
48a 37
43 35
1 0
1 0
0 0
1 0
4 2
2 0
2 1
2 1
9
7
1
1
0
1
1
1
1
0
2
1
0
0
0
0
1
1
0
1
Abbreviations: CCRT, concurrent chemoradiotherapy; IC, induction chemotherapy; NED, no evaluable disease. a Exclusion of patient A40, who had apparent complete response after both IC and CCRT but died 5 days after completing CCRT = 48 patients. b Early post-CCRT failure = residual oncologic disease identified less than 1.5 months after CCRT completion. c Post-CCRT complete response followed by failure = residual oncologic disease identified between 5.3 and 15.1 months after CCRT completion.
primary site and also developed liver metastases. Patient A41 had an FDG-avid cervical node identified on PET scan at 9.2 months post-CCRT. He underwent salvage neck dissection that identified 1 lymph node with squamous cell carcinoma. He was well and the neck dissection appeared to have been curative at follow-up appointment 10 months post-CCRT but was lost to follow-up thereafter. Patient A18 had failure at the primary site as well as liver metastases and died 4.3 months post-CCRT. Both of these patients had a positive history of smoking. Of the patients with HPV-/p16+ cancer, 1/11 (9.1%) exhibited an oncologic failure (A9). He had both primary site and distant (lung) oncologic failure, resulting in a 9% rate of primary site failure and 9% rate of distant site metastasis. He also had a positive smoking history. There were only 2 patients in this study with HPV-/p16cancer. Both had a history of smoking and both failed treatment. One failed at primary site and neck, dying 8 months post-CCRT (A20). The other was cured of locoregional disease but developed lung metastases (A27). After prolonged chemotherapy to control his lung metastases, patient A27 died 31.47 months post–primary CCRT.
Discussion Concurrent chemoradiotherapy is a widely accepted, nonsurgical treatment for advanced (stage III and IV) opSCCA, demonstrating superior locoregional control and survival compared to radiation therapy alone.7-11 In contrast, the role of IC for head and neck SCCA remains controversial. Induction chemotherapy followed by radiation alone has been shown to offer advantages over single modality radiation in studies involving opSCCA.12,13 Paccagnella et al13 demonstrated decreased distant metastases with improved locoregional control and survival with IC followed by radiation. This study did not include groups treated with CCRT or IC-CRT, however.
Subsequent studies of other head and neck cancers raised questions as to the benefit of IC in head and neck SCCA. ROTG 91-11 showed CCRT produced superior local control when compared to both radiation alone and IC followed by radiation.1 However, ROTG 91-11 included only laryngeal cancers and should not be directly extrapolated to opSCCA. In 2009, a large meta-analysis14 was published that included opSCCA and other head and neck sites. It compared CCRT to IC followed by radiation. The authors identified better locoregional control among patients receiving CCRT.14 Their analysis did not completely refute the use of IC followed by radiation, since the patients receiving IC did seem to show decreased distant metastases.14 As noted above, available evidence has tended to favor CCRT over IC followed by radiation alone. Another use for IC is so-called sequential chemotherapy utilizing IC followed by CCRT (IC-CRT) and is the subject of this study. Major prospective studies have shown favorable results utilizing this regime.3,4 The TAX 324 trial compared 2 groups of patients receiving IC-CRT. They found that the group treated with a taxane as part of the IC had better survival.4 The TAX 324 trial did not compare IC-CRT to CCRT without induction. Its focus was only on determining the benefit of a taxane in these induction regimes. In 2010, Paccagnella et al15 published a phase II trial that did compare sequential treatment with IC-CRT to CCRT without IC. In this study, the group receiving IC-CRT had a higher rate of complete response compared to the group receiving CCRT without IC.15 The PARADIGM and DeCIDE trials have been conducted to further evaluate the potential benefits of IC-CRT. At present time, neither has been able to report a clear survival benefit of IC-CRT compared to CCRT.16,17 The 49 patients reviewed in our study all received IC regimes that included a taxane in addition to a platinum based chemotherapeutic agent. Our standard IC agents were paclitaxel-carboplatin and 36 patients received this regime. This treatment decision was initially influenced by an
370
Right Tonsil T3N0M0 HPV- p16+ Smoker
Right Tonsil T4N2cM0 HPV+ p16+ Smoker
Right OP T4N0M0 HPV- p16- Smoker
Left Tonsil T3N1M0 HPV- p16- Smoker
Right Tonsil T2N2bM0 HPV+ p16+ Smoker
A9
A18
A20
A27
A41
Paclitaxel/ carboplatin
Paclitaxel/ carboplatin
Paclitaxel/ carboplatin/ cetuximab Paclitaxel/ carboplatin
Paclitaxel/ carboplatin
Paclitaxel/ carboplatin
IC Regimen
Complete clinical response
Carboplatin/ fluorouracil/ radiation
Carboplatin/ radiation
Paclitaxel/ carboplatin/ radiation Carboplatin/ fluorouracil/ radiation
Partial clinical response Partial clinical response Complete clinical response
Cisplatin/ fluorouracil/ radiation Cisplatin/ fluorouracil/ radiation
CCRT Regimen
Complete clinical response No response
Response to IC
Complete clinical & radiographic response Complete clinical & radiographic response Complete clinical & radiographic response
Complete clinical response Complete clinical & radiographic response Progressive disease
Initial Response to CCRT
Local, 15.1; distant, 19.6
Local, 1.36; distant, 1.43 Local, 5.3; neck, 5.3
11
Local (tonsil), distant (lung)
Local (tonsil), distant (liver) Local (OP), neck
Distant (lung)
9.2
N/A
N/A
Neck
Time From CCRT to Oncologic Failure (Months)
Location of Oncologic Failure
Abbreviations: BOT, base of tongue; CCRT, concurrent chemoradiotherapy; IC, induction chemotherapy; OP, oropharynx.
BOT T3N3M0 HPV+ p16+ Nonsmoker
A40
Patient
Primary TNMHPV p16 Smoking
Table 8. Treatment Failures.
PET scan
PET scan
Local, CT; neck, CT
Local, physical exam; distant, chest CT Local, CT; distant, PET
N/A
Identification of Oncologic Failure
Salvage neck dissection (1 node with +SCCA)
Secondary chemotherapy
Secondary chemotherapy
Secondary IC followed by secondary CCRT N/A
N/A
Salvage Treatment
32.5
Unknown Disease free at last follow-up (10 months post-CCRT)
8
4.3
22.73
0.17
Died with active disease
Died with active disease
Died with active disease
Died of pulmonary embolism 5 days postCCRT Died with active disease
Status
Post-CCRT Survival (Months)
Flavill et al article from Vokes et al.18 In their study, 69 patients were treated with this IC regimen followed by CCRT with good results. TAX 324 subsequently compared TPF to cisplatinfluorouracil.4,19 Paclitaxel-carboplatin was continued as the basic IC treatment in our series because of the favorable outcomes and toxicity profiles observed (see Tables 4 and 7). TPF was used in the IC treatment of 2 patients in our series. One of these patients was switched to paclitaxelcarboplatin due to febrile neutropenia that developed after the first dose of TPF. He went on to tolerate paclitaxel-carboplatin for 3 additional treatments. Both of these patients ultimately did well with no evidence of oncologic failure at last follow-up. TPF was used for IC in these patients for a combination of insurance reasons and outside facility consultant recommendations. Chronologically later in our series, cetuximab was added to the basic IC of paclitaxel-carboplatin for patients with bulky T4 disease and 11 patients received at least 1 dose. A trial published by Kies et al20 had supported this practice by reporting excellent disease control. Cetuximab dosing varied from 1 to 6 doses in our series because it was discontinued if patients developed a significant skin rash. In 2011, the RTOG 0522 phase III trial21 presented their results, which failed to show any benefit from the inclusion of cetuximab to platinum based CCRT. The role of cetuximab as a part of an IC treatment with sequential CCRT remains undefined. Among the 11 patients that received cetuximab during IC in our study, 10 (91%) had a durable complete response. This can be compared to the group that received paclitaxel and carboplatin alone, in which 31 out of a total 36 patients (86%) had a durable complete response to treatment. An obvious limitation is the smaller number of patients in the cetuximab group. Overall, both groups had outcomes that compared favorably to published trials.11 Cisplatin was the radiation-sensitizing agent of choice for CCRT in our series. The bulk of historical data supports the use of cisplatin and there are limited data comparing cisplatin to carboplatin during radiation.22,23 Patients were switched over to carboplatin during CCRT if they experienced significant toxicity (renal, neurologic, functional decline). Patients with prior renal, neurologic, or functional status deficits were given carboplatin based CCRT from the start. Eighteen patients from chronologically earlier in the series received fluorouracil in addition to a platinum based agent during CCRT. Fluorouracil was dropped from the CCRT regime in the face of studies suggesting it did not improve treatment outcomes.24 One patient (A18) received paclitaxel-carboplatin for CCRT at an outside facility. This patient is included in the interest of completeness and represents an oncologic failure (see Table 8). The choice of therapeutic agents for IC and CCRT reported represent treatment plans and not a controlled trial designed to answer 1 scientific question. A limitation of this study is the fact that these treatment plans changed over
371 time as a result of treatment successes, publication of new data, clinical experience, and patient tolerance/complications. The groups receiving different agents were not sufficiently large or balanced to allow for meaningful comparison within this study. Instead, these data represent our realworld experience treating this population with IC-CRT. A complete durable response was achieved in 43/48 (89.6%) of our patients with average follow-up of 46.8 months (mean follow-up 42.6 months). This result is encouraging in comparison to published studies.11 Of course, the lack of full 5-year follow-up on all patients and the retrospective nature of this study must be considered when assessing these results. Increased toxicity has also been 1 of the major concerns regarding sequential treatment with IC-CRT.25 Our results for toxicity/side effects compare favorably to published studies.18,26 Our rate of neurotoxicity after IC-CRT was acceptable, with 68% of patients remaining asymptomatic. Thrombotic and infectious complications were also similar to previously reported rates. Side effect profiles at last available follow-up were similarly acceptable (see Table 6). The majority of patients (70%) were able to eat all foods without difficulty. Only 4% were limited to a liquid or non-oral diet. In contrast, CCRT outcomes have reported 18% complete dysphagia and gastrostomy tube dependence.27 Significant taste disturbance was present in only 21% of patients with available followup, while xerostomia was quite prevalent at 85%, comparable to CCRT without IC.28 These data are also limited by a lack of full 5-year follow-up on all patients. While these outcomes and toxicity profiles were favorable, it is important to consider the HPV and p16 status of the tumors being treated. Improved response rates and prognoses have been well documented for HPV+/p16+ opSCCA.4-6 In addition, studies have shown HPV-/p16+ tumors also have an improved prognosis when compared to tumors that are HPV-/p16-.29,30 For this reason, all of the patients included in this study were required to have an adequate specimen for HPV and p16 testing. Our results were surprising, in that 36 out of the total 49 patients were HPV+/p16+. Of the remaining patients, another 11 (22%) were HPV-/p16+. Only 2 patients (4%) were found to be HPV-/p16-. These results are despite comparable proportions of smokers (28 patients) and nonsmokers (21 patients). These findings highlight the importance of HPV and p16 testing when evaluating treatments for opSCCA. It is somewhat dramatic that out of 49 patients with opSCCA, only 2 were HPV-/p16-. While this group is too small for a meaningful comparison, both of these patients failed treatment and died of oncologic disease. Considering the published data on HPV and p16 status, our outcomes have likely been positively influenced by the high number of HPV+/p16+ and HPV-/p16+ tumors. The skewed proportions of HPV and p16 represent a significant finding and provide a strong
372 argument for obtaining both HPV and p16 testing in both clinical practice and research studies. In either setting, lack of this information could prove misleading when assessing the relative efficacy of treatment strategies for opSCCA.
Conclusions Sequential chemotherapy with IC-CRT, as evaluated in this study, has favorable cure rates and acceptable toxicity profiles. It is significant that 73% of our patients were HPV+/ p16+. Another 22% were HPV-/p16+. This illustrates the importance of obtaining HPV and p16 testing with opSCCA as favorable outcomes may be influenced by a high prevalence of HPV+/p16+ positive tumors. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Research was supported with funds from American Airlines through the American Airlines Professorship in Cancer Research. No sponsors or funders had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.
References 1. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349:2091-2098. 2. Posner M. Options in the Treatment of Head and Neck Cancer. Manhasset, NY: CMPMedica, The Oncology Group; 2006. 3. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357(17),1695-1704. 4. Lorch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomized phase 3 trial. Lancet Oncol. 2011;12:153-159. 5. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24. 6. Rischin D, Young RJ, Fisher R, et al. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol. 2010;28:4142-4148. 7. Forastiere AA, Trotti A. Radiotherapy and concurrent chemotherapy: a strategy that improves locoregional control and survival in oropharyngeal cancer. J Natl Cancer Inst. 1999;91:2065-2066.
Annals of Otology, Rhinology & Laryngology 123(5) 8. Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemoradiotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst. 1999;91:2081-2086. 9. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol. 2004;22:69-76. 10. Adelstein DJ, Lavertu P, Saxton JP, et al. Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer. 2000;88:876-883. 11. Blanchard P, Baujat B, Holostenco V, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol. 2011;100:33-40. 12. Domenge C, Hill C, Lefebvre JL, et al. Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. Br J Cancer. 2000;83:1594-1598. 13. Paccagnella A, Orlando A, Marchiori C, et al. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst. 1994;86:265-272. 14. Pignon JP, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92(1): 4-14. 15. Paccagnella A, Ghi MG, Loreggian L, et al. Concomitant chemoradiotherapy versus induction docetaxel, cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: a phase II randomized study. Ann Oncol. 2010;21:15151522. 16. Haddad R, Rabinowits G, Tishler R, et al. The PARADIGM trial: a phase III study comparing sequential therapy (ST) to concurrent chemoradiotherapy (CRT) in locally advanced head and neck cancer (LANHC). J Clin Oncol. 2012;30(suppl):5501. 17. Cohen E, Karrison T, Kocherginsky M, et al. DeCIDE: a phase III randomized trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F) (TPF) induction chemotherapy (IC) in patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol. 2012;30(suppl):5500. 18. Vokes EE, Stenson K, Rosen FR, et al. Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: curative and organpreserving therapy for advanced head and neck cancer. J Clin Oncol. 2003;21:320-326. 19. Posner M, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357:1705-1715. 20. Kies MS, Holsinger FC, Lee JJ, et al. Induction chemotherapy and cetuximab for locally advanced squamous cell carcinoma of the head and neck: results from a phase II prospective trial. J Clin Oncol. 2010;28:8-14.
Flavill et al 21. Ang KK, Zhang QE, Rosenthal DI, et al. A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC). J Clin Oncol. 2011;29:360s. 22. Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003;21:92-98. 23. Lokich J, Anderson N. Carboplatin versus cisplatin in solid tumors: an analysis of the literature. Ann Oncol. 1998;9: 13-21. 24. Pignon J, Maître A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92:4-14. 25. Kumar S, Datta NR, Ahuja RC, Mali HR, Agarwal GN, Ayyagari S. Feasibility of non-cisplatin-based induction chemotherapy and concurrent chemoradiotherapy in advanced head and neck cancer. Acta Oncol. 1996;35:721-725.
373 26. Hitt R, Paz-Ares L, Brandariz A, et al. Induction chemotherapy with paclitaxel, cisplatin and 5-fluorouracil for squamous cell carcinoma of the head and neck: long-term results of a phase II trial. Ann Oncol. 2002;13:1665-1673. 27. Greven KM, White DR, Browne JD, et al. Swallowing dysfunction is a common sequelae after chemoradiation for oropharynx carcinoma. Am J Clin Oncol. 2008;31: 209-212. 28. Hancock SB, Krempl GA, Canfield V, et al. Treatment of base of tongue cancer with paclitaxel, ifosfamide, and cisplatinum induction chemotherapy followed by chemoradiotherapy. Laryngoscope. 2008;118:1357-1361. 29. Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus–associated oropharyngeal cancers with favorable prognosis. J Clin Oncol. 2006;24:736-747. 30. Weinberger PM, Yu Z, Kountourakis P, et al. Defining molecular phenotypes of human papillomavirus–associated oropharyngeal squamous cell carcinoma: validation of three-class hypothesis. Otolaryngol Head Neck Surg. 2009;141:382-389.
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research-article2014
AORXXX10.1177/0003489414526685Annals of Otology, Rhinology & LaryngologyFlavill et al
Article
Induction Chemotherapy Followed by Concurrent Chemoradiotherapy for Advanced Stage Oropharyngeal Squamous Cell Carcinoma With HPV and P16 Testing
Annals of Otology, Rhinology & Laryngology 2014, Vol. 123(5) 365–373 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003489414526685 aor.sagepub.com
Eric Flavill, MD1, Yisheng V. Fang, MD, PhD2, Brett Miles, DDS, MD1,3, John Truelson, MD1, and Steve Perkins, MD4
Abstract Objective: The objective was to report our experience with advanced stage oropharyngeal squamous cell carcinoma treated sequentially with induction chemotherapy followed by concurrent chemoradiotherapy. Methods: Retrospective chart review identified 49 eligible patients with advanced stage oropharyngeal squamous cell carcinoma treated with induction chemotherapy followed by concurrent chemoradiotherapy. HPV and p16INK4A testing was performed on pathology specimens. Follow-up of over 11 months was required unless a death or treatment failure occurred before that time. Results: Treatment with induction chemotherapy followed by concurrent chemoradiotherapy resulted in 44/48 (90%) complete durable response. One death occurred from pulmonary embolism. Toxicity profiles were comparable to other published data. Average follow-up was 3.9 years. Oncologic failure rates among subgroups showed 5.7% failure for HPV+/ p16+ cancer, 9.1% failure for HPV-/p16+ cancer, 100% failure for HPV-/p16- cancer, 0% failure for nonsmokers, and 17.9% failure for smokers. Conclusions: This study showed favorable outcomes in terms of durable oncologic response and acceptable toxicity profiles. It is notable that 36/49 patients were HPV+/p16+ and 11/49 were HPV-/p16+. Only 2 patients were HPV-/p16-, and both died as a result of oncologic failures. This highlights the importance of obtaining HPV and p16 testing in studies evaluating the efficacy of treatments for oropharyngeal squamous cell carcinoma. Keywords oropharyngeal squamous cell carcinoma, induction chemotherapy, sequential chemotherapy, human papilloma virus, p16 Although concurrent chemoradiotherapy (CCRT) is widely accepted treatment for advanced stage oropharyngeal squamous cell carcinoma (opSCCA), induction chemotherapy (IC) remains controversial. ROTG 91-11 demonstrated IC followed by radiotherapy produced inferior local control for laryngeal cancer compared to CCRT.1 Based on ROTG 91-11 and other studies, CCRT became the nonsurgical treatment of choice for advanced head and neck cancer.2 Subsequently, 2 large studies (TAX 323 and TAX 324) demonstrated positive outcomes using an IC regime that included a taxane.3,4 TAX 324 specifically evaluated IC followed by CCRT (IC-CRT).4 IC-CRT has since gained additional attention as a treatment modality for these patients. At the same time, the prognostic importance of human papilloma virus (HPV) and p16INK4A status for the oropharyngeal subsite has become well recognized.4-6 Because of the significant impact of HPV and p16INK4A status, it is possible
that studies regarding the efficacy of any given treatment modality for opSCCA could be significantly skewed by these factors. This retrospective chart review reports our experience with advanced opSCCA treated with IC-CRT. Disease free survival, side effect/toxicity profiles, and HPV/ p16INK4A status are reported. 1
Department of Otolaryngology/Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA 2 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA 3 Mount Sinai Hospital, New York, New York, USA 4 Hematology/Oncology, Baylor Medical Center, Dallas, Texas, USA Corresponding Author: Eric Flavill, MD, Department of Otolaryngology/Head and Neck Surgery, University of Texas Southwestern Medical Center, PO Box 72, Wilmington, OH 45177, USA. Email: [email protected]
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Materials and Methods
Table 1. Patient Clinical Characteristics (49 Patients Evaluated).
This is a retrospective review of patients diagnosed with advanced stage opSCCA who received primary IC-CRT. Approval was obtained from the UT Southwestern Medical Center institutional review board. Inclusion criteria were as follows: (1) diagnosis of stage III or IV opSCCA between January 1, 2003, and June 1, 2009, (2) no history of prior chemotherapy or radiotherapy, (3) no prior surgical treatment of the cancer, (4) pathology specimen for HPV and p16INK4A testing, (5) no definitive distant metastases at initiation of treatment, (6) adequate follow-up records, and (7) IC-CRT with curative intent. Patients were required to have over 11 months follow-up. If treatment failure or death occurred, the patient was included in the study regardless of follow-up. Patients were excluded if they were under 18 years old, pregnant, or mentally handicapped. A database of patients receiving CCRT was used to identify 246 potentially suitable patient records. These charts provided 49 patients that satisfied inclusion criteria. Study patients were randomly assigned a reference code from A01 to A49 to allow for clear description of treatment failures in the results and discussion sections. Pathology specimens were reviewed to confirm diagnosis and adequacy of the available specimen. HPV testing was then performed using the family 16 in-situ hybridization probe (F16) which detects HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 66. We utilized the INFORM HPV III Family 16 Probe (B) by Ventana Medical Systems, Inc (Tucson, Arizona, USA). Qualitative p16INK4A immunohistochemical testing was performed with CINtec Histology V-Kit from mtm laboratories, Inc (Westborough, Massachusetts, USA). The IC used consisted of paclitaxel-carboplatin, paclitaxel-carboplatin-cetuximab, or docetaxel-cisplatin-fluorouracil (TPF). Thirty patients received 6 courses of paclitaxel-carboplatin. These medications were given weekly for 6 weeks. Due to treatment complications some patients received only 5, 4, or 3 weekly doses of induction paclitaxel-carboplatin. One patient received a single dose of TPF then 4 doses of paclitaxel-carboplatin. Another patient received TPF for 3 weekly doses. The remaining patients received 4-6 doses of paclitaxel-carboplatin with 1-6 associated cetuximab doses. Patients received filgrastim 4-5 days after each dose of IC. They were given premedication with diphenhydramine, ondansetron, ranitidine, and dexamethasone prior to IC doses. Patients were started on CCRT approximately 2 weeks after completing IC. CCRT treatments included cisplatinfluorouracil, cisplatin alone, carboplatin alone, cisplatinfluorouracil followed by carboplatin-fluorouracil, and cisplatin followed by carboplatin. The radiation component consisted of intensity modulated radiotherapy (IMRT). Patients received 60-72 Gy to the primary site and 50-55 Gy
Patient Clinical Characteristics Age at diagnosis, y Mean Median Range Sex Male Female Smoking history No Yes Mean, pack-yearsa Median, pack-yearsa Range, pack-yearsa Ethanol use None Occasional/mild Moderate/heavy Medical comorbidity present at diagnosis Hypertension Diabetes Coronary artery disease ECOG performance status at diagnosis 0, asymptomatic 1, symptomatic, fully ambulatory 2, symptomatic, in bed < 50% of the day 3, symptomatic, in bed > 50% of the day but not bedridden 4, bedridden 5, dead
No. (%) 55.43 53.94 35.71-77.74 45 (92) 4 (8) 21 (43) 28 (57) 37.5 35 2-105 14 (28) 23 (47) 12 (25) 16 (33) 4 (8) 6 (12) 38 (78) 8 (16) 2 (4) 1 (2) 0 (0) 0 (0)
a
Patient A08 used cigars and pipe and so is counted as a smoker, but pack-year history data are not available, so he is not included in mean, median, and range data for pack-years.
to the neck. Radiation fractions ranged from 30 to 34 fractions over 38 to 49 days.
Results A total of 49 patients met inclusion criteria and had sufficient pathology specimens for HPV and p16INK4A testing. One patient (A40) died 5 days after completing CCRT. He is excluded from oncologic outcome data but is included in patient demographic and initial IC data. This left 48 patients for late toxicity and long-term oncologic outcome data. Table 1 shows patient demographics and comorbidities. Patients are divided into 3 groups by HPV and p16INK4A status: (1) HPV positive/p16 positive (HPV+/p16+), (2) HPV negative/p16 positive (HPV-/p16+), (3) HPV negative/p16 negative (HPV-/p16-). HPV/p16 data are reported in Table 2. Notably, there were only 2 patients (4%) in the HPV-/ p16- group. No patients were HPV positive and p16INK4A
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Flavill et al Table 2. Patient Pathologic Characteristics for Oncologic Outcome Group (48 Patients Evaluated).a Patient Pathological Characteristics
No. (%)
HPV positive HPV negative P16 positive P16 negative Smoking history No Yes HPV positive/p16 positive HPV negative/p16 positive HPV negative/p16 negative
35 (73) 13 (27) 46 (96) 2 (4) 20 (42) 28 (58) 35 (73) 11 (23) 2 (4)
a Patient A40 excluded due to death 5 days post-CCRT (he was HPV+/ p16+ and a nonsmoker).
Table 4. Toxicity of Induction Regimen (49 Patients Evaluated). Neuropathy from Induction Chemotherapy
No. (%)
0 = None 1 = Paresthesias and/or decreased deep tendon reflexes 2 = Severe paresthesias and/or mild weakness 3 = Intolerable paresthesias and/or motor loss 4 = Paralysis Infection/thrombosis from induction chemotherapy 0 = None 1 = Sepsis 2 = Mediport infection 3 = Phlebitis, local cellulitis 4 = Deep venous thrombosis
26 (53) 9 (18) 13(27) 1 (2) 42 (86) 2 (4) 2 (4) 1 (2) 4 (8)
Table 3. Staging (49 Patients Evaluated). Primary Tumor Site and Staging Site of primary tumor Tonsil Base of tongue Oropharynx Stage of primary tumor T1 T2 T3 T4 Nodal stage N0 N1 N2a N2b N2c N3 Overall stage of disease I II III IV
No. (%) 21 (43) 26 (53) 2 (4) 3 (6) 16 (33) 21 (43) 9 (18) 4 (8) 8 (16) 2 (4) 20 (41) 12 (25) 3 (6) 0 (0) 0 (0) 10 (0) 39 (80)
negative. Tumor site and staging are shown in Table 3. Two patients were labeled oropharynx because the subsite could not be distinguished.
Toxicity and Side Effects Table 4 shows documented toxicity during and immediately after IC. Table 5 reports toxicity during or shortly after CCRT. One patient (A40) died of a pulmonary embolism from a deep venous thrombosis 5 days after completing CCRT. Symptomatic mucositis was present in all but 1
Table 5. Toxicity of Concurrent Chemoradiotherapy Regimen (49 Patients Evaluated). Neuropathy
No. (%)
0 = None 1 = Paresthesias and/or decreased deep tendon reflexes 2 = Severe paresthesias and/or mild weakness 3 = Intolerable paresthesias and/or motor loss 4 = Paralysis Infection/thrombosis 0 = None 1 = Sepsis 2 = Mediport infection 3 = Phlebitis, local cellulitis 4 = Deep venous thrombosis 5 = Deep venous thrombosis/pulmonary embolism Mucositis 0 = None 1 = Erythema/soreness 2 = Ulcers/erythema ability to eat solids 3 = Ulcers, required liquid diet 4 = Unable to maintain nutrition PO Nutritional status during therapy 0 = Oral adequate 1 = PEG 2 = TPN 3 = TPN/PEG
33 (68) 5 (10) 9 (18) 2 (4) 0 (0) 27 (55) 4 (8) 9 (18) 2 (4) 13 (27) 4 (8)
1 (2) 2 (4) 2 (4) 17 (35) 27 (55) 16 (33) 15 (31) 14 (28) 4 (8)
Abbreviations: PEG, percutaneous endoscopic gastrostomy; PO, per ss; TPN, total parenteral nutrition.
patient during CCRT. Fourteen patients required total parenteral nutrition (TPN) during CCRT and 4 of them also
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Table 6. Posttreatment Toxicity Profile at Last Follow-Up (49 Patients Evaluated).a Dysphagia
No. (%)
33 (68) 6 (12) 6 (12) 1 (2) 1 (2) 2 (4)
0 = All foods without difficulty 1 = Solid foods with some difficulty 2 = Soft or semisolid foods only 3 = Liquids only 4 = No foods/saliva N/A = Patient expired before long-term outcome data could be established Xerostomia 0 = None/mild 1 = Clinically significant/symptomatic N/A = Patient expired before long-term outcome data could be established Taste disturbance 0 = None/mild 1 = Yes/significant N/A = Patient expired before long-term outcome data could be established Osteoradionecrosis 0 = None 1 = Yes N/A = Patient expired before long-term outcome data could be established
7 (14) 40 (82) 2 (4)
37 (76) 10 (20) 2 (4)
46 (94) 1 (2) 2 (4)
a Toxicity profile present at last follow-up was available for 47 patients with a range of 8 to 95 months after completing induction chemotherapy followed by concurrent chemoradiotherapy. Patients A40 and A18 both died before posttreatment toxicity data could be obtained and are recorded in the table under N/A.
received gastrostomy tube. TPN was attempted to avoid gastrostomy tube or to provide nutrition while awaiting gastrostomy tube placement. The side effect profile available at last follow-up is shown in Table 6. Thirty-three of the 47 patients with available data were able to eat all foods without difficulty at their last clinical follow-up. Twelve of the remaining patients were either taking solids with some difficulty or eating soft foods. Only 1 patient was unable to take anything by mouth. Taste disturbance was also limited in this study population. Thirty-seven of the 47 patients had either no taste disturbance or only mild disturbance. Xerostomia was prevalent, however, with 40 of the 47 patients experiencing clinically significant dry mouth symptoms.
Initial Clinical Response to Induction and Correlation With Long-Term Outcome Clinical assessment of response to treatment was performed at the completion of induction therapy. CT scans were not
routinely employed for this purpose, so these data are primarily derived from physical examination and flexible laryngoscopy. The results are shown in Table 7. A complete clinical response to IC occurred in 38/49 patients. The patient who died of a pulmonary embolism 5 days after completing CCRT was in this group (A40), leaving 37 patients. Of these 37 patients, 35 went on to have durable complete responses. Nine patients had only a partial clinical response to IC. Seven of these partial responders had a complete durable response after CCRT and were free of oncologic disease at last follow-up. Only 2 patients had no response to IC. One of these patients had a durable complete response after CCRT. The other had an initial complete response to CCRT but subsequently failed at both primary and distant (lung) sites. He ultimately died of sequelae from his opSCCA.
Overall Response and Discussion of Treatment Failures Of the 49 patients in this study, 1 died of a pulmonary embolism 5 days after completing CCRT (A40). This patient had an apparent complete response to treatment. He is excluded from oncologic outcome data as it cannot be determined if this response would have been durable. Fortythree of the remaining 48 patients (89.6%) had durable complete responses documented after IC-CRT. All were alive and disease-free as of our most current follow-up data. Average follow-up for these patients was 46.8 months (3.9 years) with a median of 42.6 months. Five patients (5/48 = 10.4%) had oncologic failures with recurrent/residual disease identified (patients A9, A18, A20, A27, and A41). One of these patients had evidence of treatment failure within the first 1.5 months post-CCRT. The other 4 patients were identified to have oncologic failure between 5.3 and 15.1 months post-CCRT. The sites of oncologic failure were 3/48 (6.25%) at primary site, 2/48 (4.17%) at the neck, and 3/48 (6.25%) at distant sites. Three of the patients failed at multiple sites (A9, A18, A20) and 2 patients failed at only 1 site (A27, A41). One of the oncologic failures was lost to follow-up (A41). The other 4 were followed until their deaths. For these 4 patients, the survival ranged from 4.3 to 31.47 months post-CCRT with an average survival of 16.62 months post-CCRT. Treatment failures are shown in Table 8. Patients with a smoking history had an oncologic failure rate of 5/28 (17.9%). The 20 lifelong nonsmokers were all free of oncologic disease at their last follow-up. Note that patient A40 is excluded from the oncologic outcome data for the nonsmoking group due to his death 5 days after completing CCRT. Among patients that had HPV+/p16+ cancer, 2/35 (5.7%) showed evidence of oncologic failure. One patient (A41) failed at the neck and the other (A18) failed at the
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Flavill et al Table 7. Initial Clinical Response to Induction Chemotherapy—Correlation to Final Outcomes.
Early PostComplete All Durable CCRT Failure,b Outcomes Cure Any Site Response to IC After CCRT All groups Complete response (NED) Partial response No reduction in tumor
Early PostCCRT Failure Early PostCCRT Failure at Neck Lymph Nodes at Primary Site
Early PostCCRT Failure at Distant Site
Post-CCRT Complete Response Followed by Failure,c Any Site
Post-CCRT Complete Response Followed by Failure at Primary Site
Post-CCRT Complete Post-CCRT Response Complete Followed by Response Failure at Followed by Failure at Neck Distant Site
48a 37
43 35
1 0
1 0
0 0
1 0
4 2
2 0
2 1
2 1
9
7
1
1
0
1
1
1
1
0
2
1
0
0
0
0
1
1
0
1
Abbreviations: CCRT, concurrent chemoradiotherapy; IC, induction chemotherapy; NED, no evaluable disease. a Exclusion of patient A40, who had apparent complete response after both IC and CCRT but died 5 days after completing CCRT = 48 patients. b Early post-CCRT failure = residual oncologic disease identified less than 1.5 months after CCRT completion. c Post-CCRT complete response followed by failure = residual oncologic disease identified between 5.3 and 15.1 months after CCRT completion.
primary site and also developed liver metastases. Patient A41 had an FDG-avid cervical node identified on PET scan at 9.2 months post-CCRT. He underwent salvage neck dissection that identified 1 lymph node with squamous cell carcinoma. He was well and the neck dissection appeared to have been curative at follow-up appointment 10 months post-CCRT but was lost to follow-up thereafter. Patient A18 had failure at the primary site as well as liver metastases and died 4.3 months post-CCRT. Both of these patients had a positive history of smoking. Of the patients with HPV-/p16+ cancer, 1/11 (9.1%) exhibited an oncologic failure (A9). He had both primary site and distant (lung) oncologic failure, resulting in a 9% rate of primary site failure and 9% rate of distant site metastasis. He also had a positive smoking history. There were only 2 patients in this study with HPV-/p16cancer. Both had a history of smoking and both failed treatment. One failed at primary site and neck, dying 8 months post-CCRT (A20). The other was cured of locoregional disease but developed lung metastases (A27). After prolonged chemotherapy to control his lung metastases, patient A27 died 31.47 months post–primary CCRT.
Discussion Concurrent chemoradiotherapy is a widely accepted, nonsurgical treatment for advanced (stage III and IV) opSCCA, demonstrating superior locoregional control and survival compared to radiation therapy alone.7-11 In contrast, the role of IC for head and neck SCCA remains controversial. Induction chemotherapy followed by radiation alone has been shown to offer advantages over single modality radiation in studies involving opSCCA.12,13 Paccagnella et al13 demonstrated decreased distant metastases with improved locoregional control and survival with IC followed by radiation. This study did not include groups treated with CCRT or IC-CRT, however.
Subsequent studies of other head and neck cancers raised questions as to the benefit of IC in head and neck SCCA. ROTG 91-11 showed CCRT produced superior local control when compared to both radiation alone and IC followed by radiation.1 However, ROTG 91-11 included only laryngeal cancers and should not be directly extrapolated to opSCCA. In 2009, a large meta-analysis14 was published that included opSCCA and other head and neck sites. It compared CCRT to IC followed by radiation. The authors identified better locoregional control among patients receiving CCRT.14 Their analysis did not completely refute the use of IC followed by radiation, since the patients receiving IC did seem to show decreased distant metastases.14 As noted above, available evidence has tended to favor CCRT over IC followed by radiation alone. Another use for IC is so-called sequential chemotherapy utilizing IC followed by CCRT (IC-CRT) and is the subject of this study. Major prospective studies have shown favorable results utilizing this regime.3,4 The TAX 324 trial compared 2 groups of patients receiving IC-CRT. They found that the group treated with a taxane as part of the IC had better survival.4 The TAX 324 trial did not compare IC-CRT to CCRT without induction. Its focus was only on determining the benefit of a taxane in these induction regimes. In 2010, Paccagnella et al15 published a phase II trial that did compare sequential treatment with IC-CRT to CCRT without IC. In this study, the group receiving IC-CRT had a higher rate of complete response compared to the group receiving CCRT without IC.15 The PARADIGM and DeCIDE trials have been conducted to further evaluate the potential benefits of IC-CRT. At present time, neither has been able to report a clear survival benefit of IC-CRT compared to CCRT.16,17 The 49 patients reviewed in our study all received IC regimes that included a taxane in addition to a platinum based chemotherapeutic agent. Our standard IC agents were paclitaxel-carboplatin and 36 patients received this regime. This treatment decision was initially influenced by an
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Right Tonsil T3N0M0 HPV- p16+ Smoker
Right Tonsil T4N2cM0 HPV+ p16+ Smoker
Right OP T4N0M0 HPV- p16- Smoker
Left Tonsil T3N1M0 HPV- p16- Smoker
Right Tonsil T2N2bM0 HPV+ p16+ Smoker
A9
A18
A20
A27
A41
Paclitaxel/ carboplatin
Paclitaxel/ carboplatin
Paclitaxel/ carboplatin/ cetuximab Paclitaxel/ carboplatin
Paclitaxel/ carboplatin
Paclitaxel/ carboplatin
IC Regimen
Complete clinical response
Carboplatin/ fluorouracil/ radiation
Carboplatin/ radiation
Paclitaxel/ carboplatin/ radiation Carboplatin/ fluorouracil/ radiation
Partial clinical response Partial clinical response Complete clinical response
Cisplatin/ fluorouracil/ radiation Cisplatin/ fluorouracil/ radiation
CCRT Regimen
Complete clinical response No response
Response to IC
Complete clinical & radiographic response Complete clinical & radiographic response Complete clinical & radiographic response
Complete clinical response Complete clinical & radiographic response Progressive disease
Initial Response to CCRT
Local, 15.1; distant, 19.6
Local, 1.36; distant, 1.43 Local, 5.3; neck, 5.3
11
Local (tonsil), distant (lung)
Local (tonsil), distant (liver) Local (OP), neck
Distant (lung)
9.2
N/A
N/A
Neck
Time From CCRT to Oncologic Failure (Months)
Location of Oncologic Failure
Abbreviations: BOT, base of tongue; CCRT, concurrent chemoradiotherapy; IC, induction chemotherapy; OP, oropharynx.
BOT T3N3M0 HPV+ p16+ Nonsmoker
A40
Patient
Primary TNMHPV p16 Smoking
Table 8. Treatment Failures.
PET scan
PET scan
Local, CT; neck, CT
Local, physical exam; distant, chest CT Local, CT; distant, PET
N/A
Identification of Oncologic Failure
Salvage neck dissection (1 node with +SCCA)
Secondary chemotherapy
Secondary chemotherapy
Secondary IC followed by secondary CCRT N/A
N/A
Salvage Treatment
32.5
Unknown Disease free at last follow-up (10 months post-CCRT)
8
4.3
22.73
0.17
Died with active disease
Died with active disease
Died with active disease
Died of pulmonary embolism 5 days postCCRT Died with active disease
Status
Post-CCRT Survival (Months)
Flavill et al article from Vokes et al.18 In their study, 69 patients were treated with this IC regimen followed by CCRT with good results. TAX 324 subsequently compared TPF to cisplatinfluorouracil.4,19 Paclitaxel-carboplatin was continued as the basic IC treatment in our series because of the favorable outcomes and toxicity profiles observed (see Tables 4 and 7). TPF was used in the IC treatment of 2 patients in our series. One of these patients was switched to paclitaxelcarboplatin due to febrile neutropenia that developed after the first dose of TPF. He went on to tolerate paclitaxel-carboplatin for 3 additional treatments. Both of these patients ultimately did well with no evidence of oncologic failure at last follow-up. TPF was used for IC in these patients for a combination of insurance reasons and outside facility consultant recommendations. Chronologically later in our series, cetuximab was added to the basic IC of paclitaxel-carboplatin for patients with bulky T4 disease and 11 patients received at least 1 dose. A trial published by Kies et al20 had supported this practice by reporting excellent disease control. Cetuximab dosing varied from 1 to 6 doses in our series because it was discontinued if patients developed a significant skin rash. In 2011, the RTOG 0522 phase III trial21 presented their results, which failed to show any benefit from the inclusion of cetuximab to platinum based CCRT. The role of cetuximab as a part of an IC treatment with sequential CCRT remains undefined. Among the 11 patients that received cetuximab during IC in our study, 10 (91%) had a durable complete response. This can be compared to the group that received paclitaxel and carboplatin alone, in which 31 out of a total 36 patients (86%) had a durable complete response to treatment. An obvious limitation is the smaller number of patients in the cetuximab group. Overall, both groups had outcomes that compared favorably to published trials.11 Cisplatin was the radiation-sensitizing agent of choice for CCRT in our series. The bulk of historical data supports the use of cisplatin and there are limited data comparing cisplatin to carboplatin during radiation.22,23 Patients were switched over to carboplatin during CCRT if they experienced significant toxicity (renal, neurologic, functional decline). Patients with prior renal, neurologic, or functional status deficits were given carboplatin based CCRT from the start. Eighteen patients from chronologically earlier in the series received fluorouracil in addition to a platinum based agent during CCRT. Fluorouracil was dropped from the CCRT regime in the face of studies suggesting it did not improve treatment outcomes.24 One patient (A18) received paclitaxel-carboplatin for CCRT at an outside facility. This patient is included in the interest of completeness and represents an oncologic failure (see Table 8). The choice of therapeutic agents for IC and CCRT reported represent treatment plans and not a controlled trial designed to answer 1 scientific question. A limitation of this study is the fact that these treatment plans changed over
371 time as a result of treatment successes, publication of new data, clinical experience, and patient tolerance/complications. The groups receiving different agents were not sufficiently large or balanced to allow for meaningful comparison within this study. Instead, these data represent our realworld experience treating this population with IC-CRT. A complete durable response was achieved in 43/48 (89.6%) of our patients with average follow-up of 46.8 months (mean follow-up 42.6 months). This result is encouraging in comparison to published studies.11 Of course, the lack of full 5-year follow-up on all patients and the retrospective nature of this study must be considered when assessing these results. Increased toxicity has also been 1 of the major concerns regarding sequential treatment with IC-CRT.25 Our results for toxicity/side effects compare favorably to published studies.18,26 Our rate of neurotoxicity after IC-CRT was acceptable, with 68% of patients remaining asymptomatic. Thrombotic and infectious complications were also similar to previously reported rates. Side effect profiles at last available follow-up were similarly acceptable (see Table 6). The majority of patients (70%) were able to eat all foods without difficulty. Only 4% were limited to a liquid or non-oral diet. In contrast, CCRT outcomes have reported 18% complete dysphagia and gastrostomy tube dependence.27 Significant taste disturbance was present in only 21% of patients with available followup, while xerostomia was quite prevalent at 85%, comparable to CCRT without IC.28 These data are also limited by a lack of full 5-year follow-up on all patients. While these outcomes and toxicity profiles were favorable, it is important to consider the HPV and p16 status of the tumors being treated. Improved response rates and prognoses have been well documented for HPV+/p16+ opSCCA.4-6 In addition, studies have shown HPV-/p16+ tumors also have an improved prognosis when compared to tumors that are HPV-/p16-.29,30 For this reason, all of the patients included in this study were required to have an adequate specimen for HPV and p16 testing. Our results were surprising, in that 36 out of the total 49 patients were HPV+/p16+. Of the remaining patients, another 11 (22%) were HPV-/p16+. Only 2 patients (4%) were found to be HPV-/p16-. These results are despite comparable proportions of smokers (28 patients) and nonsmokers (21 patients). These findings highlight the importance of HPV and p16 testing when evaluating treatments for opSCCA. It is somewhat dramatic that out of 49 patients with opSCCA, only 2 were HPV-/p16-. While this group is too small for a meaningful comparison, both of these patients failed treatment and died of oncologic disease. Considering the published data on HPV and p16 status, our outcomes have likely been positively influenced by the high number of HPV+/p16+ and HPV-/p16+ tumors. The skewed proportions of HPV and p16 represent a significant finding and provide a strong
372 argument for obtaining both HPV and p16 testing in both clinical practice and research studies. In either setting, lack of this information could prove misleading when assessing the relative efficacy of treatment strategies for opSCCA.
Conclusions Sequential chemotherapy with IC-CRT, as evaluated in this study, has favorable cure rates and acceptable toxicity profiles. It is significant that 73% of our patients were HPV+/ p16+. Another 22% were HPV-/p16+. This illustrates the importance of obtaining HPV and p16 testing with opSCCA as favorable outcomes may be influenced by a high prevalence of HPV+/p16+ positive tumors. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Research was supported with funds from American Airlines through the American Airlines Professorship in Cancer Research. No sponsors or funders had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.
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