Oral Oncology 50 (2014) 560–564
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Is radiation dose reduction the right answer for HPV-positive head and neck cancer? Randall J. Kimple ⇑, Paul M. Harari 1 Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
a r t i c l e
i n f o
Article history: Available online 14 October 2013 Keywords: Head and neck cancer Human papillomavirus Radiation Dose reduction
s u m m a r y Patients with head and neck squamous cell carcinoma (HNC) related to human papillomavirus (HPV) represent a growing and distinct patient cohort with unique molecular and epidemiologic characteristics. These patients have markedly improved survival outcomes compared to those with traditional HNC, leading some to advocate for treatment dose reduction. In this article, we review ongoing clinical trials investigating several ways to reduce therapeutic intensity for patients with HPV-positive HNC, discuss the risks and benefits associated with these trials, and summarize the data underlying the advancement of dose reduction trials for patients with HPV-positive HNC. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Human papillomavirus (HPV) is associated with up to one third of all head and neck squamous cell carcinomas (HNC) and 50–80% of cancers arising in the oropharynx [1,2]. Patients with HPV-positive HNC represent a distinct patient cohort with unique characteristics [3–11]. With current trends, it is estimated that HPV-positive HNC will become the dominant etiologic factor for HNC during the coming decades [12]. In this article summarize current data suggesting that patients with HPV-positive HNC have markedly improved survival outcomes that may warrant treatment dose reduction, summarize ongoing clinical trials for patients with HPV-positive HNC, describe potential risks and benefits associated with treatment dose reduction, and provide suggestions for future approaches. Compared to patients with HPV-negative HNC, those with HPVpositive HNC commonly present at a younger age and with a more advanced neck disease [13]. Despite this, numerous clinical reports provide striking evidence of improved outcomes in patients with HPV-positive HNC compared to those with HPV-negative HNC [3–10] (reviewed in [11,14]). The majority of these reports have utilized a combination of immunohistochemistry for p16 and in situ hybridization for high-risk HPV types to identify patients as HPV-positive. Both p16 and HPV status share prognostic
⇑ Corresponding author. Address: 3107 WIMR, 1111 Highland Avenue, Madison, WI 53705, USA. Tel.: +1 (608) 263 8500; fax: +1 (608) 263 9947. E-mail addresses: [email protected] (R.J. Kimple), [email protected]. edu (P.M. Harari). 1 Address: K4/336 CSC, 600 Highland Avenue, Madison, WI 53792, USA. Tel.: +1 (608) 263 5009; fax: +1 (608) 262 6256. 1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.09.015
significance despite the 15–20% false positive and false negative rate for p16 testing as a surrogate for HPV [15,16]. Several groups have suggested that p16 status retains prognostic significance even in the absence of coincident HPV positivity [4–6,16]. In many of these studies, tumor HPV status is the strongest independent determinant of local and regional control, disease specific survival, and overall survival.
Ongoing clinical trials for patients with HPV-positive HNC On the basis of the improved survival outcomes seen in patients with HPV-positive HNC, discussions within the major cooperative groups that enroll HNC patients such as the Radiation Therapy Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (ECOG), as well as in head and neck tumor boards across the world, have considered the possibility of dose reduction in patients with HPV-positive HNC. The goals of this approach are to maintain the currently good survival outcomes while minimizing treatment-related morbidity. The trials designed to date vary considerably in their approach: induction chemotherapy with response adapted radiation; alternatives to cisplatin given concurrently with radiation; limiting radiation dose; and integrating minimally invasive surgery into the treatment algorithm. The RTOG has rapidly accrued patients to a phase III trial randomizing patients to cisplatin vs. cetuximab given concurrent with 70 Gy radiation (Fig. 1). This study hopes to answer conclusively whether cetuximab can be safely substituted for cisplatin in patients with HPV-positive HNC. In addition, important quality of life metrics are being collected to examine the potential differences in toxicity profiles that may accompany these two treatment approaches. Over 700 patients will to accrue to this important
R.J. Kimple, P.M. Harari / Oral Oncology 50 (2014) 560–564
Schema for RTOG 1016 Eligibility squamous cell carcinoma of oropharynx HPV positive by IHC for p16 T1/2 N2a/3 or T3/4 any N
Stratify Tumor stage: T1/2 vs. 3/4 Nodal stage: N0-2a vs. 2b-3 Performance status: 0 vs. 1 Smoking history: 10 pack-years
RANDOMIZE
Accelerated IMRT 70 Gy/6 wks cisplatin 100mg/m2 days 1, 22
Accelerated IMRT 70 Gy/6 wks cetuximab 8 doses
Fig. 1. Trial schema for RTOG 1016.
study by Sept 2013, and there is ongoing consideration to expand the enrollment further at the time of this writing. The University of Warwick is leading a similar study in the UK also randomizing HPV-positive HNC patients to cetuximab vs. cisplatin with concurrent radiation. Several groups are currently pursuing some form of dose reduction in patients with HPV-positive HNC (Table 1). The ECOG 1308 study was a phase II trial that recently completed accrual and utilized induction chemotherapy to select patients for radiation dose modification (from 66–70 Gy to 54 Gy based on whether they achieved a complete response to induction therapy). While induction chemotherapy is not considered a standard treatment approach in this setting, using it to select patients for dose reduction has been pursued successfully in several other diseases. Several other groups are pursuing variations on the approach of using response-adapted radiation following induction chemotherapy (Table 1). For now this remains an experimental approach, as there is no clear data that HPV-positive HNCs are more sensitive to chemotherapy than HPV-negative HNCs, or that rapid response of tumors predicts for improved radiation sensitivity or improved outcomes in HNC.
561
Several groups are also pursuing Phase 2 studies investigating some form of therapy dose reduction without induction chemotherapy. The University of Michigan is studying the use of cetuximab + standard dose radiation as an approach to decrease toxicity. This is based, at least in part, on extrapolation of data from the Bonner study suggesting that patients showing greatest benefit from cetuximab + radiation were those with oropharyngeal tumors. While this approach is attractive, the ultimate alteration in toxicity profiles between cetuximab and cisplatin may be modest and there is little data showing that cetuximab alone is efficacious in HPV-positive HNC. At the University of North Carolina (UNC) researchers are studying reduced dose radiation (from 70 Gy to 60 Gy) + weekly cisplatin (30 mg/m2) in patients with HPV-positive HNC. While still very early, the UNC trial has shown promising preliminary results in 18 patients who undergo a mandatory posttreatment biopsy of the primary site and a supra-selective neck dissection to the pre-therapy involved neck (personal communication, Dr. Bhishamjit Chera, Univ of North Carolina). Three additional randomized trials investigating patients with HPV-positive HNC are currently pending initiation or underway in the US (Table 1). Mount Sinai is leading a group of institutions randomizing 365 patients with HPV-positive HNC to one of two treatment regimens: carboplatin + cetuximab with 56 Gy radiation vs. carboplatin and 70 Gy radiation. This trial, which alters both radiation dose and chemotherapy does not include a standard of care treatment arm, but would be expected to have decreased toxicity compared to standard of care therapy. The ECOG 3311 trial has recently been NCI-approved and is a randomized phase 2 study (projected accrual is 377 patients) investigating whether upfront surgical excision and pathologic staging of all clinically evident disease can permit reduced-dose adjuvant therapy. Various resection techniques are permitted, including transoral robotic surgery (TORS), transoral laser microsurgery (TLM), or traditional headlight excision with neck dissection, with risk stratifying of patients on the basis of T stage, N stage, surgical margins, extent of extracapsular extension (ECE), and number of positive lymph nodes. Patients receive either observation (low risk pathologic stage I-II cohort); 66 Gy radiation and weekly cisplatin (high risk cohort or positive margins, extensive >1 mm ECE, or P5 metastatic lymph nodes) or are randomized to 50 Gy vs. 60 Gy IMRT (intermediate risk cohort, consisting of minor
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Is radiation dose reduction the right answer for HPV-positive head and neck cancer? Randall J. Kimple ⇑, Paul M. Harari 1 Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
a r t i c l e
i n f o
Article history: Available online 14 October 2013 Keywords: Head and neck cancer Human papillomavirus Radiation Dose reduction
s u m m a r y Patients with head and neck squamous cell carcinoma (HNC) related to human papillomavirus (HPV) represent a growing and distinct patient cohort with unique molecular and epidemiologic characteristics. These patients have markedly improved survival outcomes compared to those with traditional HNC, leading some to advocate for treatment dose reduction. In this article, we review ongoing clinical trials investigating several ways to reduce therapeutic intensity for patients with HPV-positive HNC, discuss the risks and benefits associated with these trials, and summarize the data underlying the advancement of dose reduction trials for patients with HPV-positive HNC. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Human papillomavirus (HPV) is associated with up to one third of all head and neck squamous cell carcinomas (HNC) and 50–80% of cancers arising in the oropharynx [1,2]. Patients with HPV-positive HNC represent a distinct patient cohort with unique characteristics [3–11]. With current trends, it is estimated that HPV-positive HNC will become the dominant etiologic factor for HNC during the coming decades [12]. In this article summarize current data suggesting that patients with HPV-positive HNC have markedly improved survival outcomes that may warrant treatment dose reduction, summarize ongoing clinical trials for patients with HPV-positive HNC, describe potential risks and benefits associated with treatment dose reduction, and provide suggestions for future approaches. Compared to patients with HPV-negative HNC, those with HPVpositive HNC commonly present at a younger age and with a more advanced neck disease [13]. Despite this, numerous clinical reports provide striking evidence of improved outcomes in patients with HPV-positive HNC compared to those with HPV-negative HNC [3–10] (reviewed in [11,14]). The majority of these reports have utilized a combination of immunohistochemistry for p16 and in situ hybridization for high-risk HPV types to identify patients as HPV-positive. Both p16 and HPV status share prognostic
⇑ Corresponding author. Address: 3107 WIMR, 1111 Highland Avenue, Madison, WI 53705, USA. Tel.: +1 (608) 263 8500; fax: +1 (608) 263 9947. E-mail addresses: [email protected] (R.J. Kimple), [email protected]. edu (P.M. Harari). 1 Address: K4/336 CSC, 600 Highland Avenue, Madison, WI 53792, USA. Tel.: +1 (608) 263 5009; fax: +1 (608) 262 6256. 1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.09.015
significance despite the 15–20% false positive and false negative rate for p16 testing as a surrogate for HPV [15,16]. Several groups have suggested that p16 status retains prognostic significance even in the absence of coincident HPV positivity [4–6,16]. In many of these studies, tumor HPV status is the strongest independent determinant of local and regional control, disease specific survival, and overall survival.
Ongoing clinical trials for patients with HPV-positive HNC On the basis of the improved survival outcomes seen in patients with HPV-positive HNC, discussions within the major cooperative groups that enroll HNC patients such as the Radiation Therapy Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (ECOG), as well as in head and neck tumor boards across the world, have considered the possibility of dose reduction in patients with HPV-positive HNC. The goals of this approach are to maintain the currently good survival outcomes while minimizing treatment-related morbidity. The trials designed to date vary considerably in their approach: induction chemotherapy with response adapted radiation; alternatives to cisplatin given concurrently with radiation; limiting radiation dose; and integrating minimally invasive surgery into the treatment algorithm. The RTOG has rapidly accrued patients to a phase III trial randomizing patients to cisplatin vs. cetuximab given concurrent with 70 Gy radiation (Fig. 1). This study hopes to answer conclusively whether cetuximab can be safely substituted for cisplatin in patients with HPV-positive HNC. In addition, important quality of life metrics are being collected to examine the potential differences in toxicity profiles that may accompany these two treatment approaches. Over 700 patients will to accrue to this important
R.J. Kimple, P.M. Harari / Oral Oncology 50 (2014) 560–564
Schema for RTOG 1016 Eligibility squamous cell carcinoma of oropharynx HPV positive by IHC for p16 T1/2 N2a/3 or T3/4 any N
Stratify Tumor stage: T1/2 vs. 3/4 Nodal stage: N0-2a vs. 2b-3 Performance status: 0 vs. 1 Smoking history: 10 pack-years
RANDOMIZE
Accelerated IMRT 70 Gy/6 wks cisplatin 100mg/m2 days 1, 22
Accelerated IMRT 70 Gy/6 wks cetuximab 8 doses
Fig. 1. Trial schema for RTOG 1016.
study by Sept 2013, and there is ongoing consideration to expand the enrollment further at the time of this writing. The University of Warwick is leading a similar study in the UK also randomizing HPV-positive HNC patients to cetuximab vs. cisplatin with concurrent radiation. Several groups are currently pursuing some form of dose reduction in patients with HPV-positive HNC (Table 1). The ECOG 1308 study was a phase II trial that recently completed accrual and utilized induction chemotherapy to select patients for radiation dose modification (from 66–70 Gy to 54 Gy based on whether they achieved a complete response to induction therapy). While induction chemotherapy is not considered a standard treatment approach in this setting, using it to select patients for dose reduction has been pursued successfully in several other diseases. Several other groups are pursuing variations on the approach of using response-adapted radiation following induction chemotherapy (Table 1). For now this remains an experimental approach, as there is no clear data that HPV-positive HNCs are more sensitive to chemotherapy than HPV-negative HNCs, or that rapid response of tumors predicts for improved radiation sensitivity or improved outcomes in HNC.
561
Several groups are also pursuing Phase 2 studies investigating some form of therapy dose reduction without induction chemotherapy. The University of Michigan is studying the use of cetuximab + standard dose radiation as an approach to decrease toxicity. This is based, at least in part, on extrapolation of data from the Bonner study suggesting that patients showing greatest benefit from cetuximab + radiation were those with oropharyngeal tumors. While this approach is attractive, the ultimate alteration in toxicity profiles between cetuximab and cisplatin may be modest and there is little data showing that cetuximab alone is efficacious in HPV-positive HNC. At the University of North Carolina (UNC) researchers are studying reduced dose radiation (from 70 Gy to 60 Gy) + weekly cisplatin (30 mg/m2) in patients with HPV-positive HNC. While still very early, the UNC trial has shown promising preliminary results in 18 patients who undergo a mandatory posttreatment biopsy of the primary site and a supra-selective neck dissection to the pre-therapy involved neck (personal communication, Dr. Bhishamjit Chera, Univ of North Carolina). Three additional randomized trials investigating patients with HPV-positive HNC are currently pending initiation or underway in the US (Table 1). Mount Sinai is leading a group of institutions randomizing 365 patients with HPV-positive HNC to one of two treatment regimens: carboplatin + cetuximab with 56 Gy radiation vs. carboplatin and 70 Gy radiation. This trial, which alters both radiation dose and chemotherapy does not include a standard of care treatment arm, but would be expected to have decreased toxicity compared to standard of care therapy. The ECOG 3311 trial has recently been NCI-approved and is a randomized phase 2 study (projected accrual is 377 patients) investigating whether upfront surgical excision and pathologic staging of all clinically evident disease can permit reduced-dose adjuvant therapy. Various resection techniques are permitted, including transoral robotic surgery (TORS), transoral laser microsurgery (TLM), or traditional headlight excision with neck dissection, with risk stratifying of patients on the basis of T stage, N stage, surgical margins, extent of extracapsular extension (ECE), and number of positive lymph nodes. Patients receive either observation (low risk pathologic stage I-II cohort); 66 Gy radiation and weekly cisplatin (high risk cohort or positive margins, extensive >1 mm ECE, or P5 metastatic lymph nodes) or are randomized to 50 Gy vs. 60 Gy IMRT (intermediate risk cohort, consisting of minor
