JGO-00327; No. of pages: 9; 4C: J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 6 ) XX X–XX X
Available online at www.sciencedirect.com
ScienceDirect
Meet the experts
Concurrent chemoradiotherapy in older adults with squamous cell head & neck cancer: Evidence and management Vivek Vermaa , Apar Kishor Gantib,⁎ a
Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA Department of Internal Medicine, Division of Oncology–Hematology, VA Nebraska Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, NE, USA
b
AR TIC LE I N FO
ABS TR ACT
Article history:
Objective: Treatment for head and neck cancers incurs substantial associated morbidities, which
Received 8 September 2015
can be of potentially greater significance in older patients. Though the geriatric population forms a
Received in revised form
substantial portion of patients with head and neck cancers, this group remains underrepresented in
6 December 2015
large clinical trials. Hence, management for this unique subpopulation remains empiric and mostly
Accepted 29 January 2016
based on data from younger patients. Materials and Methods: Review of key publications on geriatric patients treated for head and neck
Keywords:
cancers.
Head and neck cancer
Conclusions: We discuss data regarding chemoradiation for head and neck cancers, as well as
Chemotherapy
management of associated side effects in this population. We encourage oncologists to treat older
Radiation therapy
patients not as a homogeneous subpopulation, but rather assess several factors associated with
Geriatrics
potential tolerance to chemoradiotherapy. Aggressive supportive treatments for chemoradiotherapy toxicities are highly encouraged in this population, and with new technical/technological developments, there is potential to continually reduce toxicity in this cohort in the future. Published by Elsevier Ltd.
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Cancer in the Older Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemoradiation in the Geriatric Patient With Head & Neck Cancer . . . . . . . . . 2.1. Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Radiation Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Concurrent Chemoradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Impact of HPV Status. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of Adverse Effects in the Geriatric Patient With Head & Neck Cancer .
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⁎ Corresponding author at: Department of Hematology/Oncology, University of Nebraska Medical Center, 987680 Nebraska Medical Center, Omaha, NE 68198, USA. Tel.: + 1 402 559 5210; fax: +1 402 559 6520. E-mail address: [email protected] (A.K. Ganti).
http://dx.doi.org/10.1016/j.jgo.2016.01.010 1879-4068/Published by Elsevier Ltd.
Please cite this article as: Verma V, Ganti AK, Concurrent chemoradiotherapy in older adults with squamous cell head & neck cancer: Evidence and management, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.01.010
2
J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 6 ) XX X–XXX
4.
Conclusions . . . . . . . . Disclosures and Conflict of Author Contributions . . . References . . . . . . . . .
. . . . . . . . . . . . Interest Statements. . . . . . . . . . . . . . . . . . . . . . . . .
. . . .
. . . .
. . . .
. . . .
1. Introduction 1.1. Cancer in the Older Patient Aging is a normal physiologic process experienced at the molecular, cellular, organ, organ system, and organismal levels. Though both genetic and environmental influences govern the development, as well as the natural history, of normal aging,1 a common theme of physiologic aging involves the loss of functional reserve in various organs and organ systems throughout the body,2 regardless of inherent or acquired dysfunction to some degree in those organs or organ systems. Aging is accompanied by relatively well-described changes at the physiologic level of nearly all organ systems, although these changes may or may not be clinically apparent.3 These changes, or loss of functional reserve, leave some patients susceptible to various diseases and medical disorders. Approximately one in seven men and one in ten women will develop cancer between the ages of 60 and 69; these rates increase to 1 in 3 and 1 in 4 respectively, in men and women 70 years and older.4 As life expectancy has risen throughout the world over the last few decades, numbers of patients with cancer have also correspondingly increased; these volumes have impacted not only medical providers, but also care facilities as well as healthcare economics80. Management of geriatric patients poses different sets of challenges for the oncologist. Despite more patients not being able to tolerate therapies [e.g. surgery, chemotherapy (CT), radiotherapy (RT)], there is a tendency at various centers to be either overly aggressive or overly conservative with therapy. It is known that older patients are known to experience greater surgical mortality,5 radiation treatment breaks,6 and incomplete courses of chemotherapy.7 Balancing these risks with attempts to cure cancer (as in the majority of older patients) involves a clinical art rather than exact science. This underscores the importance of selecting which patients benefit most from more and less aggressive therapies. The use of a comprehensive geriatric assessment8 weighs several factors into determining the aggressiveness of therapy, including life expectancy and survival, cancer type, adverse effects, symptomatic considerations, and psychological tolerance of therapies.9 However, the comprehensive geriatric assessment (CGA) is cumbersome to administer routinely in a busy clinic; simplified, easy-to-administer tools are currently being evaluated for this purpose. Head and neck cancers are a prime example of neoplasms for which, due to local anatomy, surgery often results in substantial morbidities and lifestyle ramifications; furthermore, owing to delicate surrounding mucosal tissues, toxicity of RT and/or CT is a major challenge regardless of age. It is known that older patients may be more sensitive to oral mucositis,10 and the concurrent use of CT with RT is known to magnify toxicities, survival improvements
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notwithstanding.11 Perhaps as a result of these data, population-based analyses have shown that older patients are more likely to get surgery-only treatments or none at all instead of dual-modality or trimodality therapy,12,13 although the use of chemoradiotherapy (CRT) as a treatment modality in older patients has increased over time.14 As a result, CRT for patients with head and neck cancers remains a particularly challenging aspect of geriatric oncology throughout high-risk areas in the world.15–18 Herein, we summarize the trials and management of CRT in head and neck cancers in efforts to specifically tailor these elements to geriatric patients.
2. Chemoradiation in the Geriatric Patient With Head & Neck Cancer 2.1. Chemotherapy It is well-known that cancer clinical trials underrepresent the geriatric population.19 Furthermore, trials recruiting geriatric patients may do so in a biased manner, preferentially including those with fewer comorbidities and higher performance status.20 As with other malignancies, the representation of older patients in clinical trials of head and neck cancers is disproportionately low as compared to the burden of disease in this age group.20,21 This could be due to investigators attempting to "select" optimal patients in which to prove a survival benefit for a given intervention, hence making inclusion criteria less broad and biased against elderly and comorbid patients. Retrospective data on CT are controversial as to whether toxicities are actually increased in older patients with various cancers.22,23 In head and neck cancers, two large clinical trials (TAX 323 and TAX 324) testing the escalation of 5-FU/cisplatin chemotherapy by adding docetaxel, were able to ascertain improvements in survival in locally advanced head and neck squamous cell carcinoma.24,25 While induction chemotherapy remains controversial in the treatment of locally advanced head and neck cancers, these trials provide an insight into the tolerability of chemotherapy in this patient population. Though increases in hematologic toxicities were noted resulting in treatment delays, the same was not true for non-hematologic toxicities, including RT-induced mucosal toxicities. Unfortunately, the proportion of older patients in these trials was too small to draw any meaningful conclusions regarding the utility of chemotherapy in this cohort. Only 10% of patients in the TAX 323 study were older than 65 years of age,24 while the median age at diagnosis was 56 years.25 In patients that are not able to receive cisplatin chemotherapy, the anti-epidermal growth factor receptor (EGFR) antibody cetuximab has been shown to improve survival outcomes.26
Please cite this article as: Verma V, Ganti AK, Concurrent chemoradiotherapy in older adults with squamous cell head & neck cancer: Evidence and management, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.01.010
J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 6 ) XX X–XX X
However, median ages of both arms in this study were 56 and 58, so applicability to the older population is limited. Since the older patient cohort has not been specifically studied in this setting, it is difficult to state that toxicities with cetuximab are lesser in this cohort. However, despite this, cetuximab is often used off-label in the post-operative setting, in patients with substantial comorbidities, poor performance status, and/or lower-than-expected life expectancy in order to provide survival benefits over RT alone, based on extrapolation of these data. A more practical approach, especially with questions regarding the role of cetuximab in HPV mediated tumors, may be to use lower doses of cisplatin weekly (30– 40 mg/m2), as this may be better tolerated without sacrificing much in terms of efficacy.27 Carboplatin has often been substituted for cisplatin in patients who are not thought to be able to tolerate cisplatin. There are no studies directly comparing these two agents in squamous cell carcinoma of the head and neck, but one study in nasopharyngeal carcinoma suggested equivalent efficacy, and increased tolerability with carboplatin.28 Thus, while concerns remain regarding the efficacy of carboplatin, it may be an option in older patients who may have impaired renal function or are unable to tolerate the increased fluid volume associated with high-dose cisplatin.
2.2. Radiation Techniques Radiotherapy is an effective measure to treat many different cancers of the head and neck,81 and retrospective studies examining elimination of prophylactic lymph nodal RT specifically in patients over 80 demonstrated that nodal recurrence rates rose from 6% to 38%.29 Retrospective RT data also consistently suggest that disease course after RT, including disease-related survival parameters, is not very much different in older and younger patients.30–33 However, key goals of the future include whether accelerated hyperfractionated (twice daily) RT regimens, though having been shown to improve outcomes in many patients, apply to older patients; a meta-analysis suggests that the benefits of these approaches in geriatric patients may be diminished.34 Additionally, radiotherapy modalities such as stereotactic body radiotherapy, with vastly shorter and more localized treatment regimens have potential, but need to be further studied.35,36 Emerging new data using proton radiotherapy for head and neck cancers, which offers increased radiation dose sparing to normal tissues, have shown ≈ 50% reductions in need for enteral feeding tube placement to aid in nutrition as compared to patients who have received IMRT.37,38 However, these are not randomized trials and further studies are needed to determine whether this modality can cause clinically decreased toxicities, which would be particularly useful to geriatric oncologists in radiation planning for older adults with locally advanced disease.
2.3. Concurrent Chemoradiation The data on the role of CRT in older patients are conflicting, especially with regard to long-term toxicity. Multiple direct
3
retrospective comparisons in older patients undergoing CRT have shown no differences in recurrences, disease-specific survival, or overall survival in older patients as compared to younger counterparts (Table 1).39–43 Prospective nonrandomized reports (Table 1)44–46 with small sample sizes and varying chemotherapy regimens have shown similar outcomes and toxicities in older patients as large randomized trials. Despite this, some retrospective studies have shown increased long-term side effects, hematologic toxicity, complications (e.g. infections), hospitalizations, feeding tube dependence, tracheostomy placement, and disability in older patients,41,47,48 while others demonstrate no differences in specific complication rates.49 Seminal trials of CRT in head and neck cancers have shown survival improvements with concurrent CRT as compared to sequential therapy alone. The EORTC 22931 trial randomized 334 patients with operable stages III–IV head and neck cancers (mostly oral cavity or oropharynx) to postoperative RT or CRT.50 CRT resulted in improved 5-year locoregional control (69% to 82%), disease-free survival improvement from 36% to 47% at 5 years, with corresponding overall survival improvement from 40% to 53% at 5 years. However, grades 3–4 toxicities nearly doubled from 21% to 41%. These data were echoed by the results of the RTOG 9501 trial, which included 459 similarly-staged patients and tested postoperative RT versus CRT.51 Improvements in the aforementioned parameters were evident, but grades 3–4 toxicities were twice as high with CRT (34% vs. 77%). However, in both of these studies the number of older patients was very small; the EORTC trial excluded patients over the age of 70, while only 6% patients in the RTOG trial were ≥ 70 years. Hence the applicability of these results to older patients is unclear. The median age of the VA Larynx trial52 was 62 years, while in the RTOG 91-11 larynx trial,53 49% of the patients were ≥ 60 years old. Toxicity results for both trials showed a substantial increase in grades 3–4 toxicities with concurrent CRT. Because surgery for head and neck cancers is known to have greater morbidity and mortality risks in the older patients (especially those with preexisting comorbidities),54– 56 larynx preservation rates in these trials are of particular importance to the geriatric population. A salient point to note (especially in the more modern RTOG 91-11 trial) is that larynx-preservation rates for sequential CT-RT (71%) and RT only (66%) arms were similar but still substantially numerically different from concurrent CRT (84%). Thus, though all three options offer 5-year larynx preservation rates over 66%, using comorbidities and life expectancy may be warranted in assessing which patients are “expected” to die of other non-cancer causes, in whom single- or dual sequential-modality treatments (which produce less toxicity as compared to concurrent CRT) could be performed. Arguably, the strongest evidence examining CRT in older patients comes from a meta-analysis.57 Using 17,346 patients from 93 randomized trials, Pignon et al. scrutinized changes in outcomes after adding CT to RT. Doing so showed improvements regardless of primary site (oral cavity, oropharynx, larynx, hypopharynx), and provided greatest benefits for patients with stages III–IV disease,
Please cite this article as: Verma V, Ganti AK, Concurrent chemoradiotherapy in older adults with squamous cell head & neck cancer: Evidence and management, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.01.010
4
Ref.
N 39
Age (yrs) — proportion
Site
Study design
Key findings No differences in relapses No differences between groups in RFS; DFS same for all groups except worse in ≥80 Negative prognostic factors: age ≥ 80, T stage, nodal involvement and non-receipt of RT 5y OS: age 80 — 35% 5y CSS: age 80 — 62% Older patients less likely to receive second course of CT and BID RT (p < 0.001) Older cohort with greater neutropenia (p = 0.048) but not resulting hospitalizations (p = 0.12) or mucosal toxicity (p = 0.45) Feeding tubes greater in older group (p = 0.009), longer dependence (p = 0.025) No differences between groups in disease specific outcomes; lower OS in older cohort Similar grades 3–4 mucositis (p = 0.09), hematologic (p = 0.25) or all toxicity (p = 0.8) No differences in treatment breaks (p = 0.79) or rates of completing treatment (p = 0.6) More weight loss in younger cohort (p = 0.03) No difference in 2y OS (p = 0.33) Older group with worse median OS and PFS (p < 0.0001) Younger patients more likely to receive concurrent CRT (p < 0.01) In stages I–II disease, older patients — worse OS and PFS In stages III–IV disease, older patients treated with multimodality therapy had similar outcomes to younger patients Toxicities: No grade 4 toxicities; grade 3 — 55% xerostomia, 25% mucositis, 15% neutropenia No RT delay; 80% received planned chemotherapy 3y LC 79%, 3y DFS — 58%, 3y OS — 64% No difference in chemotherapy dose intensity (p = 0.22), response rates (p = 0.24), or toxicity (p = 0.74) In patients with poor performance status, older patients had a longer time to progression (16.2 vs. 8.1 months; p = 0.045) Completion rate of S-1 72% and RT 100% Grade 3 toxicity: mucositis — 20%, neutropenia — 12%, 36% required feeding tube Complete response: stage III — 93%; stage IV — 54% 2y DSS: Stage III — 92%; stage IV — 38% 2y OS: stage III — 75%; stage IV — 29%
Reizenstein
945
Available online at www.sciencedirect.com
ScienceDirect
Meet the experts
Concurrent chemoradiotherapy in older adults with squamous cell head & neck cancer: Evidence and management Vivek Vermaa , Apar Kishor Gantib,⁎ a
Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA Department of Internal Medicine, Division of Oncology–Hematology, VA Nebraska Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, NE, USA
b
AR TIC LE I N FO
ABS TR ACT
Article history:
Objective: Treatment for head and neck cancers incurs substantial associated morbidities, which
Received 8 September 2015
can be of potentially greater significance in older patients. Though the geriatric population forms a
Received in revised form
substantial portion of patients with head and neck cancers, this group remains underrepresented in
6 December 2015
large clinical trials. Hence, management for this unique subpopulation remains empiric and mostly
Accepted 29 January 2016
based on data from younger patients. Materials and Methods: Review of key publications on geriatric patients treated for head and neck
Keywords:
cancers.
Head and neck cancer
Conclusions: We discuss data regarding chemoradiation for head and neck cancers, as well as
Chemotherapy
management of associated side effects in this population. We encourage oncologists to treat older
Radiation therapy
patients not as a homogeneous subpopulation, but rather assess several factors associated with
Geriatrics
potential tolerance to chemoradiotherapy. Aggressive supportive treatments for chemoradiotherapy toxicities are highly encouraged in this population, and with new technical/technological developments, there is potential to continually reduce toxicity in this cohort in the future. Published by Elsevier Ltd.
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Cancer in the Older Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemoradiation in the Geriatric Patient With Head & Neck Cancer . . . . . . . . . 2.1. Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Radiation Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Concurrent Chemoradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Impact of HPV Status. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of Adverse Effects in the Geriatric Patient With Head & Neck Cancer .
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⁎ Corresponding author at: Department of Hematology/Oncology, University of Nebraska Medical Center, 987680 Nebraska Medical Center, Omaha, NE 68198, USA. Tel.: + 1 402 559 5210; fax: +1 402 559 6520. E-mail address: [email protected] (A.K. Ganti).
http://dx.doi.org/10.1016/j.jgo.2016.01.010 1879-4068/Published by Elsevier Ltd.
Please cite this article as: Verma V, Ganti AK, Concurrent chemoradiotherapy in older adults with squamous cell head & neck cancer: Evidence and management, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.01.010
2
J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 6 ) XX X–XXX
4.
Conclusions . . . . . . . . Disclosures and Conflict of Author Contributions . . . References . . . . . . . . .
. . . . . . . . . . . . Interest Statements. . . . . . . . . . . . . . . . . . . . . . . . .
. . . .
. . . .
. . . .
. . . .
1. Introduction 1.1. Cancer in the Older Patient Aging is a normal physiologic process experienced at the molecular, cellular, organ, organ system, and organismal levels. Though both genetic and environmental influences govern the development, as well as the natural history, of normal aging,1 a common theme of physiologic aging involves the loss of functional reserve in various organs and organ systems throughout the body,2 regardless of inherent or acquired dysfunction to some degree in those organs or organ systems. Aging is accompanied by relatively well-described changes at the physiologic level of nearly all organ systems, although these changes may or may not be clinically apparent.3 These changes, or loss of functional reserve, leave some patients susceptible to various diseases and medical disorders. Approximately one in seven men and one in ten women will develop cancer between the ages of 60 and 69; these rates increase to 1 in 3 and 1 in 4 respectively, in men and women 70 years and older.4 As life expectancy has risen throughout the world over the last few decades, numbers of patients with cancer have also correspondingly increased; these volumes have impacted not only medical providers, but also care facilities as well as healthcare economics80. Management of geriatric patients poses different sets of challenges for the oncologist. Despite more patients not being able to tolerate therapies [e.g. surgery, chemotherapy (CT), radiotherapy (RT)], there is a tendency at various centers to be either overly aggressive or overly conservative with therapy. It is known that older patients are known to experience greater surgical mortality,5 radiation treatment breaks,6 and incomplete courses of chemotherapy.7 Balancing these risks with attempts to cure cancer (as in the majority of older patients) involves a clinical art rather than exact science. This underscores the importance of selecting which patients benefit most from more and less aggressive therapies. The use of a comprehensive geriatric assessment8 weighs several factors into determining the aggressiveness of therapy, including life expectancy and survival, cancer type, adverse effects, symptomatic considerations, and psychological tolerance of therapies.9 However, the comprehensive geriatric assessment (CGA) is cumbersome to administer routinely in a busy clinic; simplified, easy-to-administer tools are currently being evaluated for this purpose. Head and neck cancers are a prime example of neoplasms for which, due to local anatomy, surgery often results in substantial morbidities and lifestyle ramifications; furthermore, owing to delicate surrounding mucosal tissues, toxicity of RT and/or CT is a major challenge regardless of age. It is known that older patients may be more sensitive to oral mucositis,10 and the concurrent use of CT with RT is known to magnify toxicities, survival improvements
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notwithstanding.11 Perhaps as a result of these data, population-based analyses have shown that older patients are more likely to get surgery-only treatments or none at all instead of dual-modality or trimodality therapy,12,13 although the use of chemoradiotherapy (CRT) as a treatment modality in older patients has increased over time.14 As a result, CRT for patients with head and neck cancers remains a particularly challenging aspect of geriatric oncology throughout high-risk areas in the world.15–18 Herein, we summarize the trials and management of CRT in head and neck cancers in efforts to specifically tailor these elements to geriatric patients.
2. Chemoradiation in the Geriatric Patient With Head & Neck Cancer 2.1. Chemotherapy It is well-known that cancer clinical trials underrepresent the geriatric population.19 Furthermore, trials recruiting geriatric patients may do so in a biased manner, preferentially including those with fewer comorbidities and higher performance status.20 As with other malignancies, the representation of older patients in clinical trials of head and neck cancers is disproportionately low as compared to the burden of disease in this age group.20,21 This could be due to investigators attempting to "select" optimal patients in which to prove a survival benefit for a given intervention, hence making inclusion criteria less broad and biased against elderly and comorbid patients. Retrospective data on CT are controversial as to whether toxicities are actually increased in older patients with various cancers.22,23 In head and neck cancers, two large clinical trials (TAX 323 and TAX 324) testing the escalation of 5-FU/cisplatin chemotherapy by adding docetaxel, were able to ascertain improvements in survival in locally advanced head and neck squamous cell carcinoma.24,25 While induction chemotherapy remains controversial in the treatment of locally advanced head and neck cancers, these trials provide an insight into the tolerability of chemotherapy in this patient population. Though increases in hematologic toxicities were noted resulting in treatment delays, the same was not true for non-hematologic toxicities, including RT-induced mucosal toxicities. Unfortunately, the proportion of older patients in these trials was too small to draw any meaningful conclusions regarding the utility of chemotherapy in this cohort. Only 10% of patients in the TAX 323 study were older than 65 years of age,24 while the median age at diagnosis was 56 years.25 In patients that are not able to receive cisplatin chemotherapy, the anti-epidermal growth factor receptor (EGFR) antibody cetuximab has been shown to improve survival outcomes.26
Please cite this article as: Verma V, Ganti AK, Concurrent chemoradiotherapy in older adults with squamous cell head & neck cancer: Evidence and management, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.01.010
J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 6 ) XX X–XX X
However, median ages of both arms in this study were 56 and 58, so applicability to the older population is limited. Since the older patient cohort has not been specifically studied in this setting, it is difficult to state that toxicities with cetuximab are lesser in this cohort. However, despite this, cetuximab is often used off-label in the post-operative setting, in patients with substantial comorbidities, poor performance status, and/or lower-than-expected life expectancy in order to provide survival benefits over RT alone, based on extrapolation of these data. A more practical approach, especially with questions regarding the role of cetuximab in HPV mediated tumors, may be to use lower doses of cisplatin weekly (30– 40 mg/m2), as this may be better tolerated without sacrificing much in terms of efficacy.27 Carboplatin has often been substituted for cisplatin in patients who are not thought to be able to tolerate cisplatin. There are no studies directly comparing these two agents in squamous cell carcinoma of the head and neck, but one study in nasopharyngeal carcinoma suggested equivalent efficacy, and increased tolerability with carboplatin.28 Thus, while concerns remain regarding the efficacy of carboplatin, it may be an option in older patients who may have impaired renal function or are unable to tolerate the increased fluid volume associated with high-dose cisplatin.
2.2. Radiation Techniques Radiotherapy is an effective measure to treat many different cancers of the head and neck,81 and retrospective studies examining elimination of prophylactic lymph nodal RT specifically in patients over 80 demonstrated that nodal recurrence rates rose from 6% to 38%.29 Retrospective RT data also consistently suggest that disease course after RT, including disease-related survival parameters, is not very much different in older and younger patients.30–33 However, key goals of the future include whether accelerated hyperfractionated (twice daily) RT regimens, though having been shown to improve outcomes in many patients, apply to older patients; a meta-analysis suggests that the benefits of these approaches in geriatric patients may be diminished.34 Additionally, radiotherapy modalities such as stereotactic body radiotherapy, with vastly shorter and more localized treatment regimens have potential, but need to be further studied.35,36 Emerging new data using proton radiotherapy for head and neck cancers, which offers increased radiation dose sparing to normal tissues, have shown ≈ 50% reductions in need for enteral feeding tube placement to aid in nutrition as compared to patients who have received IMRT.37,38 However, these are not randomized trials and further studies are needed to determine whether this modality can cause clinically decreased toxicities, which would be particularly useful to geriatric oncologists in radiation planning for older adults with locally advanced disease.
2.3. Concurrent Chemoradiation The data on the role of CRT in older patients are conflicting, especially with regard to long-term toxicity. Multiple direct
3
retrospective comparisons in older patients undergoing CRT have shown no differences in recurrences, disease-specific survival, or overall survival in older patients as compared to younger counterparts (Table 1).39–43 Prospective nonrandomized reports (Table 1)44–46 with small sample sizes and varying chemotherapy regimens have shown similar outcomes and toxicities in older patients as large randomized trials. Despite this, some retrospective studies have shown increased long-term side effects, hematologic toxicity, complications (e.g. infections), hospitalizations, feeding tube dependence, tracheostomy placement, and disability in older patients,41,47,48 while others demonstrate no differences in specific complication rates.49 Seminal trials of CRT in head and neck cancers have shown survival improvements with concurrent CRT as compared to sequential therapy alone. The EORTC 22931 trial randomized 334 patients with operable stages III–IV head and neck cancers (mostly oral cavity or oropharynx) to postoperative RT or CRT.50 CRT resulted in improved 5-year locoregional control (69% to 82%), disease-free survival improvement from 36% to 47% at 5 years, with corresponding overall survival improvement from 40% to 53% at 5 years. However, grades 3–4 toxicities nearly doubled from 21% to 41%. These data were echoed by the results of the RTOG 9501 trial, which included 459 similarly-staged patients and tested postoperative RT versus CRT.51 Improvements in the aforementioned parameters were evident, but grades 3–4 toxicities were twice as high with CRT (34% vs. 77%). However, in both of these studies the number of older patients was very small; the EORTC trial excluded patients over the age of 70, while only 6% patients in the RTOG trial were ≥ 70 years. Hence the applicability of these results to older patients is unclear. The median age of the VA Larynx trial52 was 62 years, while in the RTOG 91-11 larynx trial,53 49% of the patients were ≥ 60 years old. Toxicity results for both trials showed a substantial increase in grades 3–4 toxicities with concurrent CRT. Because surgery for head and neck cancers is known to have greater morbidity and mortality risks in the older patients (especially those with preexisting comorbidities),54– 56 larynx preservation rates in these trials are of particular importance to the geriatric population. A salient point to note (especially in the more modern RTOG 91-11 trial) is that larynx-preservation rates for sequential CT-RT (71%) and RT only (66%) arms were similar but still substantially numerically different from concurrent CRT (84%). Thus, though all three options offer 5-year larynx preservation rates over 66%, using comorbidities and life expectancy may be warranted in assessing which patients are “expected” to die of other non-cancer causes, in whom single- or dual sequential-modality treatments (which produce less toxicity as compared to concurrent CRT) could be performed. Arguably, the strongest evidence examining CRT in older patients comes from a meta-analysis.57 Using 17,346 patients from 93 randomized trials, Pignon et al. scrutinized changes in outcomes after adding CT to RT. Doing so showed improvements regardless of primary site (oral cavity, oropharynx, larynx, hypopharynx), and provided greatest benefits for patients with stages III–IV disease,
Please cite this article as: Verma V, Ganti AK, Concurrent chemoradiotherapy in older adults with squamous cell head & neck cancer: Evidence and management, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.01.010
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Ref.
N 39
Age (yrs) — proportion
Site
Study design
Key findings No differences in relapses No differences between groups in RFS; DFS same for all groups except worse in ≥80 Negative prognostic factors: age ≥ 80, T stage, nodal involvement and non-receipt of RT 5y OS: age 80 — 35% 5y CSS: age 80 — 62% Older patients less likely to receive second course of CT and BID RT (p < 0.001) Older cohort with greater neutropenia (p = 0.048) but not resulting hospitalizations (p = 0.12) or mucosal toxicity (p = 0.45) Feeding tubes greater in older group (p = 0.009), longer dependence (p = 0.025) No differences between groups in disease specific outcomes; lower OS in older cohort Similar grades 3–4 mucositis (p = 0.09), hematologic (p = 0.25) or all toxicity (p = 0.8) No differences in treatment breaks (p = 0.79) or rates of completing treatment (p = 0.6) More weight loss in younger cohort (p = 0.03) No difference in 2y OS (p = 0.33) Older group with worse median OS and PFS (p < 0.0001) Younger patients more likely to receive concurrent CRT (p < 0.01) In stages I–II disease, older patients — worse OS and PFS In stages III–IV disease, older patients treated with multimodality therapy had similar outcomes to younger patients Toxicities: No grade 4 toxicities; grade 3 — 55% xerostomia, 25% mucositis, 15% neutropenia No RT delay; 80% received planned chemotherapy 3y LC 79%, 3y DFS — 58%, 3y OS — 64% No difference in chemotherapy dose intensity (p = 0.22), response rates (p = 0.24), or toxicity (p = 0.74) In patients with poor performance status, older patients had a longer time to progression (16.2 vs. 8.1 months; p = 0.045) Completion rate of S-1 72% and RT 100% Grade 3 toxicity: mucositis — 20%, neutropenia — 12%, 36% required feeding tube Complete response: stage III — 93%; stage IV — 54% 2y DSS: Stage III — 92%; stage IV — 38% 2y OS: stage III — 75%; stage IV — 29%
Reizenstein
945
