- Email: [email protected]
Palliative Radiation Therapy for Advanced Head and Neck Carcinomas: A Phase 2 Study
Accepted Manuscript Palliative radiotherapy for advanced head and neck carcinomas, a phase II study Bernard Fortin, MD, MSc, Nader Khaouam, MD, Edith Filion, MD, Phuc Felix NguyenTan, MD, Alexis Bujold, MD, Louise Lambert, MD PII:
S0360-3016(16)00060-2
DOI:
10.1016/j.ijrobp.2016.01.039
Reference:
ROB 23398
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 3 September 2015 Revised Date:
14 January 2016
Accepted Date: 20 January 2016
Please cite this article as: Fortin B, Khaouam N, Filion E, Nguyen-Tan PF, Bujold A, Lambert L, Palliative radiotherapy for advanced head and neck carcinomas, a phase II study, International Journal of Radiation Oncology • Biology • Physics (2016), doi: 10.1016/j.ijrobp.2016.01.039. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Palliative radiotherapy for advanced head and neck carcinomas, a phase II study.
Bernard Fortin MD, MSc, corresponding author Radiation Oncology, Maisonneuve-Rosemont Hospital, 5415 L’Assomption Street, Montréal, QC, CANADA, H1T 2M4 Phone: (514) 252-3425, Fax: (514) 252-3556 Email: [email protected] Conflict of interest: none.
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Authors
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Nader Khaouam, MD Radiation Oncology, Maisonneuve-Rosemont Hospital, Montréal, QC, CANADA Conflict of interest: none.
Edith Filion, MD Radiation Oncology, Centre Hospitalier de l’Université de Montréal, QC, CANADA Conflict of interest: none. Phuc Felix Nguyen-Tan, MD Radiation Oncology, Centre Hospitalier de l’Université de Montréal, QC, CANADA Conflict of interest: none.
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Alexis Bujold, MD Radiation Oncology, Maisonneuve-Rosemont Hospital, Montréal, QC, CANADA Conflict of interest: none.
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Louise Lambert, MD Radiation Oncology, Centre Hospitalier de l’Université de Montréal, QC, CANADA Conflict of interest: none.
ClinicalTrials.gov Identifier: NCT02460471
Funding
Supported in part by a professorial support grant from the University of Montreal.
Acknowledgements The authors wish to thank the patients who participated in this study and the research staff (C Lafleur and D Trudel) who allowed us to achieve these very high completion rates for the QOL data and the perfect follow-up.
Pall iat ive RT for ad va nced H &N ca ncer
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Palliative radiotherapy for advanced head and neck carcinomas, a phase II study.
Summary
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Palliative radiation therapy (RT) may be underused in advanced head and neck cancer because of its toxicity and the paucity of evidence supporting its benefits. This is a phase II study evaluating a palliative conformal RT regimen of 25 Gy in 5 fractions with complete quality of life and toxicity recording, demonstrating both excellent tolerability and adequate symptom control.
Pall iat ive RT for ad va nced H &N ca ncer
Summary
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Palliative radiotherapy for advanced head and neck carcinomas, a phase II study. Keywords: Clinical Protocols, Head and Neck Neoplasms, Humans, Palliative Care, Prospective Studies, Quality of Life, Self-Report, Radiotherapy, IMRT
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Abstract Purpose/Objectives
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Incurable head and neck cancer is hard to manage with usual palliative care. Radiation therapy (RT) in this setting is sometimes omitted as there is an apprehension that the side effects in the head and neck region might counterbalance the benefits. The objective of this phase II study was to evaluate whether highly conformal RT could improve the therapeutic ratio with this
Methods and Materials
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comprehensive Quality of Life (QOL) and toxicity evaluation.
Patients from two academic centers, deemed unfit for radical treatment due to poor medical
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condition or advanced cancer stage by an experienced tumor board were offered 25 Gy in 5 daily IMRT fractions over one week to the symptomatic tumor volume. QOL was evaluated with
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EORTC QLQ-C15-PAL and QLQ-H&N35 questionnaires, and toxicities with CTCAE v 4.0. Survival and time to tumor progression were calculated with the Kaplan-Meier method. Results
Thirty-two patients were recruited, of which 66% had at least T4, N3 or M1 disease. The QOL questionnaires completion rate was 86%. Eighty-eight percent of patients received the planned dose. Median overall and progression free survival were respectively 6.5 and 3.2 months. No grade 4 or 5 toxicity was seen. Only 13% of patients had any grade 3 toxicities and 17% of Pall iat ive RT for ad va nced H &N ca ncer
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patients reported no toxicity at all. QOL was equal or improved, and head and neck symptoms remained equal or lower than the baseline values for most patients at up to 6 months. Eighty-
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five percent of patients would have chosen to receive this RT regimen again when asked. Conclusions
This palliative RT regimen was highly tolerable and effective in preserving or improving selfreported QOL in most patients for up to 6 months, which corresponds to this population’s
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median overall survival. Given the minimal side effects, intensification could be considered to
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achieve longer loco-regional control.
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Introduction Radiation Therapy (RT) is a potent treatment modality in Head and Neck neoplasms but is
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associated with significant side effects. Usual contra-indications to a curative radiation treatment course include extensive bone or cartilage involvement, distant metastases, poor medical condition, or patient unwillingness to endure the toxicity of standard chemo-radiation,
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which occasionally reaches death in as much as 2% of patients1.
For patients ineligible for definitive treatment, progressive head and neck cancer can be a
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source of extremely distressing symptoms. With distant disease usually a late event, patients often endure a progressive neck encasement, speech, swallowing and breathing impairment, severe pain, and isolation due to halitosis and apparent disease2.
Few medications exist to control the symptoms other than pain and helping these patients
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remains a challenge for Palliative Care Units and all those involved in their care. The role of RT in a palliative setting in advanced head and neck cancer used to be the focus of much debate. In a review from the late 1990’s3, the authors could not conclude on either the
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indications for palliative RT, if any, or on the appropriate dose to use. Combined with the fact that toxicity was not addressed by the existing literature, they concluded that studies evaluating
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clinical endpoints and patient selection were needed before recommending palliative RT in head and neck cancer patients. In this context, few patients received palliative RT at our institutions because of the belief that by the time the side effects of RT abated, the tumor was again progressing leading to no overall gain in Quality of Life (QOL). As new literature began to appear in the mid-2000, this paradigm began to change. After reviewing some of the available literature4-11, we decided to re-evaluate our position on palliative head and neck RT. In our centres, non-metastatic patients able to receive more than Pall iat ive RT for ad va nced H &N ca ncer
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45 to 50 Gy are offered a full RT regimen. We thus selected an intermediate dose (the IQ5 regimen, for Imrt for Quality of life, 5 fractions) which could be given over one week to patients unable or unwilling to tolerate a three-week or more regimen, but resulting in as few side
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effects as possible, using modern delivery techniques (IMRT, Intensity Modulated RT) otherwise considered standard in a curative setting. In order to obtain the highest possible gain in QOL,
IMRT was chosen since it is reported to have less impact on QOL than 3D-planning in head and
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neck patients12 and is planned and delivered almost as fast as 3D-RT in a high-volume centre. We wanted to be able to re-irradiate patients if needed, and we also wanted to collect a
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complete set of patient-reported QOL data using this fractionation while documenting progression free survival (PFS) and overall survival (OS).
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Patients and methods
This phase II study was offered to patients aged 18 or older who were not pregnant, able to give an informed consent and complete QOL questionnaires. The other main inclusion criteria was
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disease deemed incurable by an experienced tumor board (distant metastases, local regional extension, comorbidities), or patient refusal to receive a curative treatment.
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Radical treatments were not considered indicated in patients who would unlikely be cured by radiation alone (i.e. who had tumours of more than 10 cm, extensive invasion of bone, laryngeal cartilage, pterygoid muscles, intracranial, or oesophagus) AND who had significant comorbidities precluding chemoradiation or surgery. Other contraindications to radical treatment were metastatic disease or a concomitant advanced neoplasm. Significant comorbidities consisted most often of poor functional status, cachexia, severe pulmonary, cardiac, or kidney disease, and age above 85 years old. Pall iat ive RT for ad va nced H &N ca ncer
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Patients who declined an otherwise indicated radical treatment were met on at least two occasions and informed about the natural history of progressive head and neck cancer. The informed consent process requires that patients are made aware of the acute and long term
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side effects of radical head and neck cancer treatment. However they are also reassured of the presence of a complete, experienced multi-disciplinary team dedicated to providing all required supportive care. Therefore, refusals are never taken lightly.
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Patients had to have a measurable, biopsy-proven squamous or salivary cancer of the head and neck region, no previous RT to the head and neck region neck, no plan to receive concomitant
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chemotherapy, and an expected survival of at least 2 months. We planned to recruit 30 patients in order to have ± 5% confidence intervals on our QOL and toxicity estimates. The protocol was offered to all eligible patients in both institutions, where we usually see in total at least 400 new cases of head and neck cancer yearly. All patients refusing were still offered best supportive
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care, as this was the standard approach in our centres at the time.
A per-protocol preliminary analysis of the toxicities was to be performed after the first 8 patients and presented to the ethics committee before pursuing recruitment. The study was to
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be stopped if any grade 4 or 5 toxicity developed or if, after the first 8 patients were analyzed, it
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was highly improbable that QOL could be maintained or improved in at least half of the patients. The primary objective was to evaluate changes in QOL using the EORTC QLQ-C15-PAL13 and H&N35 module of the QLQ-C3014 questionnaires and the toxicities associated with this RT regimen using a standard grading scale, the CTCAE v 4.015. Toxicities were graded by the treating physician at each of the follow-up visits. Secondary objectives were the progression-free and overall survival from the date of recruitment using the Kaplan-Meier method16, based on intentto-treat. Follow-up physical examination and QOL questionnaires were done monthly for the
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first 6 months, every two months during the rest of the first year and every three months until 2 years post-RT. Patients were also asked at 1, 3, 6, 12 and 24 months if, knowing the benefits
decision to accept the treatment. No imaging was mandated. Radiation planning
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obtained and the side effects experienced with this RT regimen, they would still have taken the
Patients were immobilized with a thermoplastic mask and scanned in treatment position.
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Radiation therapy consisted of 25 Gy in 5 daily fractions over one week with 6 MV photons using Intensity Modulated Radiation Therapy (IMRT) on a conventional linear accelerator. Radiation
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was delivered to the tumor volume considered to cause most of the patient’s symptoms with a 5 mm margin (Planning Target Volume, PTV) to account for daily setup error. Distant tumor deposits not considered to affect the patient’s QOL could be excluded from the radiation field to reduce the treatment related toxicity at the discretion of the treating physician. The PTV had to
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receive at least 95% of the planned dose and no point was allowed to receive more than 115%. Doses to the adjacent organs at risk (OAR) were recorded in case of an unexpected toxicity. No constraints were pre-specified other than 25 Gy maximum point dose to the spinal cord and “as
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low as reasonably achievable” for the other OAR. The protocol was approved by the scientific and ethics committees at both institutions and is
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registered on clinicaltrials.gov.
Results
Between August 2011 and May 2014, we recruited the first 32 consecutive eligible patients who accepted the protocol, whose characteristics are shown in table 1. The cohort had a median age of 74, a KPS of 70-80 in 72% of cases but also had advanced cancer with 66% of patients having Pall iat ive RT for ad va nced H &N ca ncer
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either T4, N3 or M1 disease17. The characteristics excluding patients from radical treatment are detailed in table 2.
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One patient died before RT initiation. Three patients dropped out of the study for reasons unrelated to toxicity, one patient receiving 15 Gy and two receiving 20 Gy, leaving 88% of
patients who received the prescribed radiation treatment. During their follow-up, four patients eventually received more RT, and only five received some chemotherapy. Additional radiation
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therapy was given to another site in the head and neck region usually using a lower dose of 20
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Gy in 5 fractions.
Potential follow-up18 was 12.2 months, and no patients were lost to follow-up. Toxicities
Details of the toxicity profile are presented in table 3. Treatments were very well tolerated with only 13 % of patients experiencing any grade 3 over the course of their follow-up, none of which
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persisted after one month. Seventeen percent of patients reported no toxicity at all. No grade 4 or 5 toxicities were seen, allowing for recruitment completion after interim analysis. At one month, 56% of patients still reported grade 1 and 2 toxicities while 44% reported no more side
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effects. These numbers remained stable afterwards, possibly related to the fact that nine
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patients were retreated with either chemotherapy or radiotherapy, making it difficult to differentiate toxicities from first and subsequent lines of treatment, and from symptoms of tumor regrowth.
Self-reported outcomes
Fearing that QOL completion rates could be low in this population, we included a simple question about patient’s satisfaction with the treatment received:
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“Considering what you know now of the benefits vs side effects of the radiation treatment you received, would you still have chosen to receive this course of RT?”
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Six patients never answered. For the others, 21 said “yes” throughout the follow-up period, five said “no” at least once, one of whom later changed his final answer to “yes” leading to an overall 85% of patients satisfied with RT.
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The QOL questionnaires were completed at 157 of the 182 planned time points, for an 86%
completion rate. Results from the most significant subscales are presented in figure 2. Most of
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the effectiveness of the radiation on QOL, physical functioning, pain, fatigue and swallowing persisted for the first 6 months. Outcomes are not reported after 6 months due to the limited number of questionnaires available for review after this time. Overall survival and progression free survival
Median overall survival was 6.5 months (figure 1), resulting in an overall survival at 1 year of
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Discussion
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30%. Median progression-free survival was 3.2 months.
Despite the fact that radiation therapy is widely used in a palliative setting for many cancers, it was rarely used in head and neck cancer in our centres because of the belief that the side effects of RT at this disease site lasted as long as its palliative benefits. This belief was not challenged until recently due to the paucity of convincing literature Mohanti et al9 reported toxicities limited to dry desquamation and patchy mucositis with improvement in around half of the patients for symptoms such as pain, dysphagia, hoarseness, Pall iat ive RT for ad va nced H &N ca ncer
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cough and otalgia using 2D planned RT delivering 20 Gy in 5 fractions. Follow-up was admittedly limited and no QOL data was collected.
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Corry et al7 developed a RT scheme (the “Quad Shot”) designed as cycles of RT doses just below the threshold for mucositis which could be repeated up to three times. They gave 14 Gy as 4 x 3.5 Gy given BID for two consecutive days repeated at 4 weekly intervals with 2D planning. In
their phase II pilot study, no grade 3 toxicity was reported. Forty-four percent of patients had an
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improvement in their self-reported QOL, 43% of the patients said that the RT was “worthwhile” after the first course and that number rose to 63% in those who received the full three courses
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(about half of the patients). PFS was 3.1 months and median survival was 5.7 months. Porceddu et al11 performed another phase II study (the “Hypo Trial”) but this time using 3D planning to deliver 30 to 36 Gy in 5 to 6 fractions given twice weekly, at least three days apart, to the symptomatic gross disease with a 1.5 to 2 cm margin, hoping to improve PFS and survival
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from the Quad Shot results. The grade 3 toxicity rate was 26% for mucositis, 11% for skin, 11% for dysphagia. Two patients (6%) with hypopharyngeal primaries developed grade 4 dysphagia. Despite this, 62% recorded an overall improvement in their QOL and 67% reported an
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improvement in overall pain. PFS was 3.9 months and median survival was 6.1 months.
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Agarwal et al4 pushed the dose to 40 Gy in 16 fractions with 2D planning. In-field progressionfree survival was much better at more than 12 months but only 78% of patients were able to tolerate the whole course of RT. Moreover, toxicity was much higher with grade 3 rates of 14% and 63% for skin and mucosae respectively, and 25% of patients required nutritional support during RT. Median survival was not reported, nor QOL data.
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Chen et al6 used a similar RT dose of 50 Gy in 16 fractions and obtained similar toxicities, grade 3 rates of 45% and 65% for skin and mucosae respectively. With this higher dose, 45% of their cohort required the placement of a feeding tube during RT.
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Monnier et al10 retrospectively reviewed charts of 78 patients treated with conventional (44%) or 3D (56%) RT to a dose of 3 Gy BID on days 1 and 3, during the first, third, fifth, and seventh
week of this “IHF2SQ” regimen, for a total of 48 Gy. Most (81%) patients received platinum or
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taxane based induction chemotherapy, and 94% also received concurrent chemotherapy.
and no QOL data was obtained.
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Although median survival was of almost 13 months, toxicities were not prospectively collected
The current study allowed us to treat a group of patients who would previously not have been referred for RT, under very close scrutiny with frequent visits and exhaustive screening for side effects and quality of life indicators.
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The toxicity profile of this RT regimen, given that it is delivered with very conformal IMRT based planning, shows that this treatment is extremely well tolerated. Carefully validated self-reported QOL questionnaires indicate that this treatment provides a stabilization or improvement of well-
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being for the majority of patients throughout the median survival of the cohort. The “IQ5” one-
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week schedule was very well tolerated, as is shown by the high completion rate and the very high degree of satisfaction towards this regimen with 85% of patients stating that they felt the treatment was worthwhile. Pushing the rationale of conformity, retrospective data published by Khan et al19 in 2015 explores the use of stereotactic body radiotherapy with doses of 35 to 48 Gy in 5 fractions. For the moment QOL data are limited. Furthermore, the tumor volumes treated in that study appeared smaller with 83% of patients receiving radiation at lymph nodes alone or skin sites, Pall iat ive RT for ad va nced H &N ca ncer
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compared to our study where both primary tumor and nodes were irradiated. It will be interesting to see if that extremely conformal radiation technique will improve the therapeutic
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ratio even more compared to IMRT as used here when longer follow-up is available. The short overall and progression-free survival in this study are partly explained by the subjects’ characteristics. The majority of patients had either advanced disease, or comorbidities
precluding radical chemoradiation or even palliative chemotherapy. Our main objective being
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QOL, we deliberately chose to only modestly increase the dose of radiation compared to the
standard 20 Gy in 5 fractions often used in a palliative setting. More than to improve survival,
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we wanted to know if by limiting irradiation of non-cancer tissues using IMRT we could reduce the side effects enough to allow patients to benefit from the temporary tumor shrinkage provided.
With this objective in mind, this study demonstrates, with toxicity and QOL data, that the
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palliative RT regimen used here is safe, well tolerated, well accepted, and effective in maintaining or improving QOL in most patients treated for most of the group’s median survival. By targeting symptomatic, macroscopically involved areas, IMRT limits acute toxicities since less
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normal tissue is irradiated to a high dose. Moreover, the PTV is smaller with IGRT use, which also reduces the volume receiving a higher dose. These results have been practice-changing in
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both our institutions, where few patients with incurable head and neck cancer were offered palliative RT a few years ago. Due to the availability of IMRT in more and more centres and the fact that with modern computers and linear accelerators an IMRT plan is calculated and delivered almost as fast as a 2D plan, this regimen allows for effective palliation with very mild toxicities, using reasonable resources, in a context of very debilitating disease where few medical options exist.
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Conclusion
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Even frail patients with incurable head and neck cancer can benefit from a short course of conformal radiotherapy to stabilize or improve their quality of life and decrease their disease-
related symptoms for a significant period of their remaining lifespan. Considering the very low
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probability of side effects with this regimen, it appears reasonable and safe to investigate if a
moderate increase in the dose of RT using the same delivery technique could improve survival,
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hopefully without sacrificing tolerability.
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References 1. Ang KK, Zhang Q, Rosenthal DI, et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin
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Oncol 2014;32:2940-50.
2. Kowalski LP, Carvalho AL. Natural history of untreated head and neck cancer. Eur J Cancer 2000;36:1032-7.
cancer. Can J Oncol 1996;6 Suppl 1:54-60.
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3. Hodson DI, Bruera E, Eapen L, et al. The role of palliative radiotherapy in advanced head and neck
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4. Agarwal JP, Nemade B, Murthy V, et al. Hypofractionated, palliative radiotherapy for advanced head and neck cancer. Radiother Oncol 2008;89:51-6.
5. Al-mamgani A, Tans L, Van rooij PH, Noever I, Baatenburg de jong RJ, Levendag PC. Hypofractionated radiotherapy denoted as the "Christie scheme": an effective means of palliating patients with head and neck cancers not suitable for curative treatment. Acta Oncol 2009;48:562-70.
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6. Chen AM, Vaughan A, Narayan S, Vijayakumar S. Palliative radiation therapy for head and neck cancer: toward an optimal fractionation scheme. Head Neck 2008;30:1586-91. 7. Corry J, Peters LJ, Costa ID, et al. The 'QUAD SHOT'--a phase II study of palliative radiotherapy for incurable head and neck cancer. Radiother Oncol 2005;77:137-42.
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8. Ghoshal S, Chakraborty S, Moudgil N, Kaur M, Patel FD. Quad shot: a short but effective schedule for palliative radiation for head and neck carcinoma. Indian J Palliat Care 2009;15:137-40.
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9. Mohanti BK, Umapathy H, Bahadur S, Thakar A, Pathy S. Short course palliative radiotherapy of 20 Gy in 5 fractions for advanced and incurable head and neck cancer: AIIMS study. Radiother Oncol 2004;71:275-80.
10. Monnier L, Touboul E, Durdux C, Lang P, St Guily JL, Huguet F. Hypofractionated palliative radiotherapy for advanced head and neck cancer: the IHF2SQ regimen. Head Neck 2013;35:1683-8.
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11. Porceddu SV, Rosser B, Burmeister BH, et al. Hypofractionated radiotherapy for the palliation of advanced head and neck cancer in patients unsuitable for curative treatment--"Hypo Trial". Radiother Oncol 2007;85:456-62.
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12. Mendenhall WM, Amdur RJ, Palta JR. Intensity-Modulated Radiotherapy in the Standard Management of Head and Neck Cancer: Promises and Pitfalls. Journal of Clinical Oncology 2006;24:2618-23.
13. Groenvold M, Petersen MA, Aaronson NK, et al. The development of the EORTC QLQ-C15-PAL: a shortened questionnaire for cancer patients in palliative care. Eur J Cancer 2006;42:55-64.
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14. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
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Journal of the National Cancer Institute 1993;85:365-76.
15. National Cancer Institute, Common Terminology Criteria for Adverse Events v4.0 NCI, NIH, DHHS May 29, 2009 2009;NIH publication # 09-7473.
16. Kaplan EL, Meier P. Nonparametric Estimation from Incomplete Observations. Journal of the American Statistical Association 1958;53:457-81.
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17. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Annals of surgical oncology 2010;17:1471-4. 18. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Controlled clinical
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trials 1996;17:343-6.
19. Khan L, Tjong M, Raziee H, et al. Role of stereotactic body radiotherapy for symptom control in head
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and neck cancer patients. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 2015;23:1099-103.
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Figure Legends
Figure 1a: Overall Survival
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Legend, figure 1a: Overall. Survival, in months, from the time of enrollment with numbers at risk. Median overall survival was 6.5 months
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Figure 1b: Progression-Free Survival.
Legend, figure 1b: Progression-free survival, in months, from the time of enrollment with
Figure 2: Patient reported outcomes
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numbers at risk. Median progression-free survival was 3.2 months.
Figure 2 legend: Proportion of patients with same or better scores vs worse scores than their baseline values in their quality of life and physical functioning scores, and proportion of patients
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with same or less problems vs more problems than their baseline values in their symptom
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scores according to the duration of follow-up in months.
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Palliative radiotherapy for advanced head and neck carcinomas, a phase II study.
Tables Table 1, patients’ characteristics
N
Histology
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Pre-existing dysphagia
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Pre-treatment feeding tube Pre-treatment tracheostomy KPS
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Oral cavity Salivary gland Larynx Nasopharynx Oropharynx Paranasal sinuses Other T0-Tx T1 T2 T3 T4 N0-Nx N1 N2 N3 M0-Mx M1 Salivary Squamous None Liquids Solids Total
Female 5 (16%) : Male 27 (84%) Median 74, range 44-90 y.o Median 72, range 19 – 311 cc 4 (13%) 2 (6%) 4 (13%) 1 (3%) 9 (28%) 3 (9%) 9 (28%)
60 70 80 90
7 (23%) 2 (7%) 2 (7%) 6 (20%) 13 (43%) 10 (33%) 1 (3%) 10 (33%) 9 (30%) 23 (74%) 8 (26%) 2 (6%) 29 (94%) 19 (61%) 1 (3%) 10 (32%) 1 (3%) 3 (9%)
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Gender Age GTV volume (cc) Primary
3 (9%) 1 (4%) 10 (36%) 13 (46%) 4 (14%)
Legend, Table 1: Patients’ characteristics. GTV is Gross Tumour Volume, the tumoral volume included in the radiation plan.
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Table 2, Motives for palliative treatment, n=32
1 massive meningeal involvement 1 T3 palate but lung transplant, severe cardiac disease, poor lung function 1 massive pterygoid muscle involvement with cardiac disease precluding chemotherapy or surgery 1 oral cavity with massive bony involvement, 81 y.o., 40 pounds weight loss, poor ECOG 8 metastatic HNSCC (stage IVc) 1 stage IV colon cancer 4 concomitant stage III-IV lung cancer 1 acute lymphoid leukemia, 83 y.o. Median age 80 (range 44-90) 86% stage IVa-b 10 with significant cardio-vascular or kidney disease
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incurable despite fit patient radically treatable lesions but significant comorbid conditions
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14 patients with distant disease
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14 patient refusal of radical treatment
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Worst toxicity After 2 month (n=21)
3 2 (7) 2 (7) 4 (13) -
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Worst toxicity After 1 month (n=23)
Skin Mucosal Laryngeal Hemorrhage Other Overall Skin Mucosal Laryngeal Hemorrhage Other Overall Skin Mucosal Laryngeal Hemorrhage Other Overall
Grade, n (%) 1 2 15 (50) 4 (13) 10 (33) 2 (7) 2 (7) 3 (10) 2 (7) 6 (20) 6 (20) 10 (33) 11 (37) 6 (30) 1 (5) 3 (14) 1 (5) 1 (5) 1 (5) 1 (5) 4 (19) 4 (19) 8 (38) 5 (24) 5 (27) 1 (6) 2 (11) 1 (6) 1 (6) 1 (6) 1 (6) 3 (17) 3 (17) 6 (33) 4 (22)
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Worst toxicity (n=31)
0 11 (37) 16 (53) 28 (93) 25 (83) 16 (53) 5 (17) 13 (65) 17 (81) 19 (95) 18 (90) 13 (62) 8 (38) 12 (67) 15 (83) 17 (94) 16 (89) 12 (67) 8 (44)
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Table 3, toxicities
Legend, table 3: worst treatment related reported toxicity as graded with the CTCAE v4.0 during
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the whole follow-up period and at 1 and 2 months after radiotherapy.
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Overall Survival 1.0 Censored
95% Confidence Limits
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0.6
0.4
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Survival
0.8
0.0 At Risk
32
9
0
10
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0.2
2
1
0
20
30
40
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months
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Progression Free Survival 1.0 Censored
95% Confidence Limits
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0.6
0.4
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Survival
0.8
0.0 At Risk
32
7
1
0
5
10
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0.2
1
1
15
20
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months
30
40
ACCEPTED MANUSCRIPT Global Quality of Life
Physical Func oning
90%
90%
80%
76% 67% 59%
60%
58%
50%
40%
42%
41%
38%
33%
35% 30%
24%
20%
62%
same or be er
73%
60% 50% 35% 29%
25%
27%
20%
25%
Head and Neck Pain
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worse
90%
83%
80% 77%
71%
70%
73%
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70%
65%
60% 50% 40%
0%
30%
23%
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10%
76%
71%
58%
58%
50%
42%
42%
40% 30%
29% 25%
24%
20%
13%
0%
same or be er
20%
60%
87%
10%
0%
30%
70%
75%
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Percentage of respondents
71%
10%
Percentage of respondents
80%
75%
Percentage of respondents
75%
29%
worse
Fa gue
90%
30%
24%
20%
Swallowing Problems
40%
25%
worse
90%
71%
42% 27%
30%
0%
65%
29%
same or be er
worse
58%
41%
38%
40%
0%
70%
59%
50%
10%
80%
73%
60%
10%
same or be er
76%
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65%
62%
75% 70%
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70%
Percentage of respondents
Percentage of respondents
80%
35%
27% 17%
same or be er
worse
S0360-3016(16)00060-2
DOI:
10.1016/j.ijrobp.2016.01.039
Reference:
ROB 23398
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 3 September 2015 Revised Date:
14 January 2016
Accepted Date: 20 January 2016
Please cite this article as: Fortin B, Khaouam N, Filion E, Nguyen-Tan PF, Bujold A, Lambert L, Palliative radiotherapy for advanced head and neck carcinomas, a phase II study, International Journal of Radiation Oncology • Biology • Physics (2016), doi: 10.1016/j.ijrobp.2016.01.039. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Palliative radiotherapy for advanced head and neck carcinomas, a phase II study.
Bernard Fortin MD, MSc, corresponding author Radiation Oncology, Maisonneuve-Rosemont Hospital, 5415 L’Assomption Street, Montréal, QC, CANADA, H1T 2M4 Phone: (514) 252-3425, Fax: (514) 252-3556 Email: [email protected] Conflict of interest: none.
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Authors
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Nader Khaouam, MD Radiation Oncology, Maisonneuve-Rosemont Hospital, Montréal, QC, CANADA Conflict of interest: none.
Edith Filion, MD Radiation Oncology, Centre Hospitalier de l’Université de Montréal, QC, CANADA Conflict of interest: none. Phuc Felix Nguyen-Tan, MD Radiation Oncology, Centre Hospitalier de l’Université de Montréal, QC, CANADA Conflict of interest: none.
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Alexis Bujold, MD Radiation Oncology, Maisonneuve-Rosemont Hospital, Montréal, QC, CANADA Conflict of interest: none.
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Louise Lambert, MD Radiation Oncology, Centre Hospitalier de l’Université de Montréal, QC, CANADA Conflict of interest: none.
ClinicalTrials.gov Identifier: NCT02460471
Funding
Supported in part by a professorial support grant from the University of Montreal.
Acknowledgements The authors wish to thank the patients who participated in this study and the research staff (C Lafleur and D Trudel) who allowed us to achieve these very high completion rates for the QOL data and the perfect follow-up.
Pall iat ive RT for ad va nced H &N ca ncer
title page
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Palliative radiotherapy for advanced head and neck carcinomas, a phase II study.
Summary
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Palliative radiation therapy (RT) may be underused in advanced head and neck cancer because of its toxicity and the paucity of evidence supporting its benefits. This is a phase II study evaluating a palliative conformal RT regimen of 25 Gy in 5 fractions with complete quality of life and toxicity recording, demonstrating both excellent tolerability and adequate symptom control.
Pall iat ive RT for ad va nced H &N ca ncer
Summary
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Palliative radiotherapy for advanced head and neck carcinomas, a phase II study. Keywords: Clinical Protocols, Head and Neck Neoplasms, Humans, Palliative Care, Prospective Studies, Quality of Life, Self-Report, Radiotherapy, IMRT
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Abstract Purpose/Objectives
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Incurable head and neck cancer is hard to manage with usual palliative care. Radiation therapy (RT) in this setting is sometimes omitted as there is an apprehension that the side effects in the head and neck region might counterbalance the benefits. The objective of this phase II study was to evaluate whether highly conformal RT could improve the therapeutic ratio with this
Methods and Materials
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comprehensive Quality of Life (QOL) and toxicity evaluation.
Patients from two academic centers, deemed unfit for radical treatment due to poor medical
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condition or advanced cancer stage by an experienced tumor board were offered 25 Gy in 5 daily IMRT fractions over one week to the symptomatic tumor volume. QOL was evaluated with
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EORTC QLQ-C15-PAL and QLQ-H&N35 questionnaires, and toxicities with CTCAE v 4.0. Survival and time to tumor progression were calculated with the Kaplan-Meier method. Results
Thirty-two patients were recruited, of which 66% had at least T4, N3 or M1 disease. The QOL questionnaires completion rate was 86%. Eighty-eight percent of patients received the planned dose. Median overall and progression free survival were respectively 6.5 and 3.2 months. No grade 4 or 5 toxicity was seen. Only 13% of patients had any grade 3 toxicities and 17% of Pall iat ive RT for ad va nced H &N ca ncer
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patients reported no toxicity at all. QOL was equal or improved, and head and neck symptoms remained equal or lower than the baseline values for most patients at up to 6 months. Eighty-
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five percent of patients would have chosen to receive this RT regimen again when asked. Conclusions
This palliative RT regimen was highly tolerable and effective in preserving or improving selfreported QOL in most patients for up to 6 months, which corresponds to this population’s
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median overall survival. Given the minimal side effects, intensification could be considered to
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achieve longer loco-regional control.
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Introduction Radiation Therapy (RT) is a potent treatment modality in Head and Neck neoplasms but is
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associated with significant side effects. Usual contra-indications to a curative radiation treatment course include extensive bone or cartilage involvement, distant metastases, poor medical condition, or patient unwillingness to endure the toxicity of standard chemo-radiation,
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which occasionally reaches death in as much as 2% of patients1.
For patients ineligible for definitive treatment, progressive head and neck cancer can be a
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source of extremely distressing symptoms. With distant disease usually a late event, patients often endure a progressive neck encasement, speech, swallowing and breathing impairment, severe pain, and isolation due to halitosis and apparent disease2.
Few medications exist to control the symptoms other than pain and helping these patients
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remains a challenge for Palliative Care Units and all those involved in their care. The role of RT in a palliative setting in advanced head and neck cancer used to be the focus of much debate. In a review from the late 1990’s3, the authors could not conclude on either the
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indications for palliative RT, if any, or on the appropriate dose to use. Combined with the fact that toxicity was not addressed by the existing literature, they concluded that studies evaluating
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clinical endpoints and patient selection were needed before recommending palliative RT in head and neck cancer patients. In this context, few patients received palliative RT at our institutions because of the belief that by the time the side effects of RT abated, the tumor was again progressing leading to no overall gain in Quality of Life (QOL). As new literature began to appear in the mid-2000, this paradigm began to change. After reviewing some of the available literature4-11, we decided to re-evaluate our position on palliative head and neck RT. In our centres, non-metastatic patients able to receive more than Pall iat ive RT for ad va nced H &N ca ncer
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45 to 50 Gy are offered a full RT regimen. We thus selected an intermediate dose (the IQ5 regimen, for Imrt for Quality of life, 5 fractions) which could be given over one week to patients unable or unwilling to tolerate a three-week or more regimen, but resulting in as few side
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effects as possible, using modern delivery techniques (IMRT, Intensity Modulated RT) otherwise considered standard in a curative setting. In order to obtain the highest possible gain in QOL,
IMRT was chosen since it is reported to have less impact on QOL than 3D-planning in head and
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neck patients12 and is planned and delivered almost as fast as 3D-RT in a high-volume centre. We wanted to be able to re-irradiate patients if needed, and we also wanted to collect a
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complete set of patient-reported QOL data using this fractionation while documenting progression free survival (PFS) and overall survival (OS).
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Patients and methods
This phase II study was offered to patients aged 18 or older who were not pregnant, able to give an informed consent and complete QOL questionnaires. The other main inclusion criteria was
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disease deemed incurable by an experienced tumor board (distant metastases, local regional extension, comorbidities), or patient refusal to receive a curative treatment.
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Radical treatments were not considered indicated in patients who would unlikely be cured by radiation alone (i.e. who had tumours of more than 10 cm, extensive invasion of bone, laryngeal cartilage, pterygoid muscles, intracranial, or oesophagus) AND who had significant comorbidities precluding chemoradiation or surgery. Other contraindications to radical treatment were metastatic disease or a concomitant advanced neoplasm. Significant comorbidities consisted most often of poor functional status, cachexia, severe pulmonary, cardiac, or kidney disease, and age above 85 years old. Pall iat ive RT for ad va nced H &N ca ncer
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Patients who declined an otherwise indicated radical treatment were met on at least two occasions and informed about the natural history of progressive head and neck cancer. The informed consent process requires that patients are made aware of the acute and long term
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side effects of radical head and neck cancer treatment. However they are also reassured of the presence of a complete, experienced multi-disciplinary team dedicated to providing all required supportive care. Therefore, refusals are never taken lightly.
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Patients had to have a measurable, biopsy-proven squamous or salivary cancer of the head and neck region, no previous RT to the head and neck region neck, no plan to receive concomitant
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chemotherapy, and an expected survival of at least 2 months. We planned to recruit 30 patients in order to have ± 5% confidence intervals on our QOL and toxicity estimates. The protocol was offered to all eligible patients in both institutions, where we usually see in total at least 400 new cases of head and neck cancer yearly. All patients refusing were still offered best supportive
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care, as this was the standard approach in our centres at the time.
A per-protocol preliminary analysis of the toxicities was to be performed after the first 8 patients and presented to the ethics committee before pursuing recruitment. The study was to
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be stopped if any grade 4 or 5 toxicity developed or if, after the first 8 patients were analyzed, it
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was highly improbable that QOL could be maintained or improved in at least half of the patients. The primary objective was to evaluate changes in QOL using the EORTC QLQ-C15-PAL13 and H&N35 module of the QLQ-C3014 questionnaires and the toxicities associated with this RT regimen using a standard grading scale, the CTCAE v 4.015. Toxicities were graded by the treating physician at each of the follow-up visits. Secondary objectives were the progression-free and overall survival from the date of recruitment using the Kaplan-Meier method16, based on intentto-treat. Follow-up physical examination and QOL questionnaires were done monthly for the
Pall iat ive RT for ad va nced H &N ca ncer
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first 6 months, every two months during the rest of the first year and every three months until 2 years post-RT. Patients were also asked at 1, 3, 6, 12 and 24 months if, knowing the benefits
decision to accept the treatment. No imaging was mandated. Radiation planning
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obtained and the side effects experienced with this RT regimen, they would still have taken the
Patients were immobilized with a thermoplastic mask and scanned in treatment position.
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Radiation therapy consisted of 25 Gy in 5 daily fractions over one week with 6 MV photons using Intensity Modulated Radiation Therapy (IMRT) on a conventional linear accelerator. Radiation
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was delivered to the tumor volume considered to cause most of the patient’s symptoms with a 5 mm margin (Planning Target Volume, PTV) to account for daily setup error. Distant tumor deposits not considered to affect the patient’s QOL could be excluded from the radiation field to reduce the treatment related toxicity at the discretion of the treating physician. The PTV had to
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receive at least 95% of the planned dose and no point was allowed to receive more than 115%. Doses to the adjacent organs at risk (OAR) were recorded in case of an unexpected toxicity. No constraints were pre-specified other than 25 Gy maximum point dose to the spinal cord and “as
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low as reasonably achievable” for the other OAR. The protocol was approved by the scientific and ethics committees at both institutions and is
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registered on clinicaltrials.gov.
Results
Between August 2011 and May 2014, we recruited the first 32 consecutive eligible patients who accepted the protocol, whose characteristics are shown in table 1. The cohort had a median age of 74, a KPS of 70-80 in 72% of cases but also had advanced cancer with 66% of patients having Pall iat ive RT for ad va nced H &N ca ncer
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either T4, N3 or M1 disease17. The characteristics excluding patients from radical treatment are detailed in table 2.
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One patient died before RT initiation. Three patients dropped out of the study for reasons unrelated to toxicity, one patient receiving 15 Gy and two receiving 20 Gy, leaving 88% of
patients who received the prescribed radiation treatment. During their follow-up, four patients eventually received more RT, and only five received some chemotherapy. Additional radiation
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therapy was given to another site in the head and neck region usually using a lower dose of 20
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Gy in 5 fractions.
Potential follow-up18 was 12.2 months, and no patients were lost to follow-up. Toxicities
Details of the toxicity profile are presented in table 3. Treatments were very well tolerated with only 13 % of patients experiencing any grade 3 over the course of their follow-up, none of which
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persisted after one month. Seventeen percent of patients reported no toxicity at all. No grade 4 or 5 toxicities were seen, allowing for recruitment completion after interim analysis. At one month, 56% of patients still reported grade 1 and 2 toxicities while 44% reported no more side
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effects. These numbers remained stable afterwards, possibly related to the fact that nine
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patients were retreated with either chemotherapy or radiotherapy, making it difficult to differentiate toxicities from first and subsequent lines of treatment, and from symptoms of tumor regrowth.
Self-reported outcomes
Fearing that QOL completion rates could be low in this population, we included a simple question about patient’s satisfaction with the treatment received:
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“Considering what you know now of the benefits vs side effects of the radiation treatment you received, would you still have chosen to receive this course of RT?”
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Six patients never answered. For the others, 21 said “yes” throughout the follow-up period, five said “no” at least once, one of whom later changed his final answer to “yes” leading to an overall 85% of patients satisfied with RT.
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The QOL questionnaires were completed at 157 of the 182 planned time points, for an 86%
completion rate. Results from the most significant subscales are presented in figure 2. Most of
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the effectiveness of the radiation on QOL, physical functioning, pain, fatigue and swallowing persisted for the first 6 months. Outcomes are not reported after 6 months due to the limited number of questionnaires available for review after this time. Overall survival and progression free survival
Median overall survival was 6.5 months (figure 1), resulting in an overall survival at 1 year of
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Discussion
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30%. Median progression-free survival was 3.2 months.
Despite the fact that radiation therapy is widely used in a palliative setting for many cancers, it was rarely used in head and neck cancer in our centres because of the belief that the side effects of RT at this disease site lasted as long as its palliative benefits. This belief was not challenged until recently due to the paucity of convincing literature Mohanti et al9 reported toxicities limited to dry desquamation and patchy mucositis with improvement in around half of the patients for symptoms such as pain, dysphagia, hoarseness, Pall iat ive RT for ad va nced H &N ca ncer
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cough and otalgia using 2D planned RT delivering 20 Gy in 5 fractions. Follow-up was admittedly limited and no QOL data was collected.
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Corry et al7 developed a RT scheme (the “Quad Shot”) designed as cycles of RT doses just below the threshold for mucositis which could be repeated up to three times. They gave 14 Gy as 4 x 3.5 Gy given BID for two consecutive days repeated at 4 weekly intervals with 2D planning. In
their phase II pilot study, no grade 3 toxicity was reported. Forty-four percent of patients had an
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improvement in their self-reported QOL, 43% of the patients said that the RT was “worthwhile” after the first course and that number rose to 63% in those who received the full three courses
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(about half of the patients). PFS was 3.1 months and median survival was 5.7 months. Porceddu et al11 performed another phase II study (the “Hypo Trial”) but this time using 3D planning to deliver 30 to 36 Gy in 5 to 6 fractions given twice weekly, at least three days apart, to the symptomatic gross disease with a 1.5 to 2 cm margin, hoping to improve PFS and survival
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from the Quad Shot results. The grade 3 toxicity rate was 26% for mucositis, 11% for skin, 11% for dysphagia. Two patients (6%) with hypopharyngeal primaries developed grade 4 dysphagia. Despite this, 62% recorded an overall improvement in their QOL and 67% reported an
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improvement in overall pain. PFS was 3.9 months and median survival was 6.1 months.
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Agarwal et al4 pushed the dose to 40 Gy in 16 fractions with 2D planning. In-field progressionfree survival was much better at more than 12 months but only 78% of patients were able to tolerate the whole course of RT. Moreover, toxicity was much higher with grade 3 rates of 14% and 63% for skin and mucosae respectively, and 25% of patients required nutritional support during RT. Median survival was not reported, nor QOL data.
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Chen et al6 used a similar RT dose of 50 Gy in 16 fractions and obtained similar toxicities, grade 3 rates of 45% and 65% for skin and mucosae respectively. With this higher dose, 45% of their cohort required the placement of a feeding tube during RT.
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Monnier et al10 retrospectively reviewed charts of 78 patients treated with conventional (44%) or 3D (56%) RT to a dose of 3 Gy BID on days 1 and 3, during the first, third, fifth, and seventh
week of this “IHF2SQ” regimen, for a total of 48 Gy. Most (81%) patients received platinum or
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taxane based induction chemotherapy, and 94% also received concurrent chemotherapy.
and no QOL data was obtained.
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Although median survival was of almost 13 months, toxicities were not prospectively collected
The current study allowed us to treat a group of patients who would previously not have been referred for RT, under very close scrutiny with frequent visits and exhaustive screening for side effects and quality of life indicators.
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The toxicity profile of this RT regimen, given that it is delivered with very conformal IMRT based planning, shows that this treatment is extremely well tolerated. Carefully validated self-reported QOL questionnaires indicate that this treatment provides a stabilization or improvement of well-
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being for the majority of patients throughout the median survival of the cohort. The “IQ5” one-
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week schedule was very well tolerated, as is shown by the high completion rate and the very high degree of satisfaction towards this regimen with 85% of patients stating that they felt the treatment was worthwhile. Pushing the rationale of conformity, retrospective data published by Khan et al19 in 2015 explores the use of stereotactic body radiotherapy with doses of 35 to 48 Gy in 5 fractions. For the moment QOL data are limited. Furthermore, the tumor volumes treated in that study appeared smaller with 83% of patients receiving radiation at lymph nodes alone or skin sites, Pall iat ive RT for ad va nced H &N ca ncer
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compared to our study where both primary tumor and nodes were irradiated. It will be interesting to see if that extremely conformal radiation technique will improve the therapeutic
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ratio even more compared to IMRT as used here when longer follow-up is available. The short overall and progression-free survival in this study are partly explained by the subjects’ characteristics. The majority of patients had either advanced disease, or comorbidities
precluding radical chemoradiation or even palliative chemotherapy. Our main objective being
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QOL, we deliberately chose to only modestly increase the dose of radiation compared to the
standard 20 Gy in 5 fractions often used in a palliative setting. More than to improve survival,
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we wanted to know if by limiting irradiation of non-cancer tissues using IMRT we could reduce the side effects enough to allow patients to benefit from the temporary tumor shrinkage provided.
With this objective in mind, this study demonstrates, with toxicity and QOL data, that the
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palliative RT regimen used here is safe, well tolerated, well accepted, and effective in maintaining or improving QOL in most patients treated for most of the group’s median survival. By targeting symptomatic, macroscopically involved areas, IMRT limits acute toxicities since less
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normal tissue is irradiated to a high dose. Moreover, the PTV is smaller with IGRT use, which also reduces the volume receiving a higher dose. These results have been practice-changing in
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both our institutions, where few patients with incurable head and neck cancer were offered palliative RT a few years ago. Due to the availability of IMRT in more and more centres and the fact that with modern computers and linear accelerators an IMRT plan is calculated and delivered almost as fast as a 2D plan, this regimen allows for effective palliation with very mild toxicities, using reasonable resources, in a context of very debilitating disease where few medical options exist.
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Conclusion
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Even frail patients with incurable head and neck cancer can benefit from a short course of conformal radiotherapy to stabilize or improve their quality of life and decrease their disease-
related symptoms for a significant period of their remaining lifespan. Considering the very low
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probability of side effects with this regimen, it appears reasonable and safe to investigate if a
moderate increase in the dose of RT using the same delivery technique could improve survival,
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hopefully without sacrificing tolerability.
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References 1. Ang KK, Zhang Q, Rosenthal DI, et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin
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Oncol 2014;32:2940-50.
2. Kowalski LP, Carvalho AL. Natural history of untreated head and neck cancer. Eur J Cancer 2000;36:1032-7.
cancer. Can J Oncol 1996;6 Suppl 1:54-60.
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3. Hodson DI, Bruera E, Eapen L, et al. The role of palliative radiotherapy in advanced head and neck
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4. Agarwal JP, Nemade B, Murthy V, et al. Hypofractionated, palliative radiotherapy for advanced head and neck cancer. Radiother Oncol 2008;89:51-6.
5. Al-mamgani A, Tans L, Van rooij PH, Noever I, Baatenburg de jong RJ, Levendag PC. Hypofractionated radiotherapy denoted as the "Christie scheme": an effective means of palliating patients with head and neck cancers not suitable for curative treatment. Acta Oncol 2009;48:562-70.
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6. Chen AM, Vaughan A, Narayan S, Vijayakumar S. Palliative radiation therapy for head and neck cancer: toward an optimal fractionation scheme. Head Neck 2008;30:1586-91. 7. Corry J, Peters LJ, Costa ID, et al. The 'QUAD SHOT'--a phase II study of palliative radiotherapy for incurable head and neck cancer. Radiother Oncol 2005;77:137-42.
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8. Ghoshal S, Chakraborty S, Moudgil N, Kaur M, Patel FD. Quad shot: a short but effective schedule for palliative radiation for head and neck carcinoma. Indian J Palliat Care 2009;15:137-40.
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9. Mohanti BK, Umapathy H, Bahadur S, Thakar A, Pathy S. Short course palliative radiotherapy of 20 Gy in 5 fractions for advanced and incurable head and neck cancer: AIIMS study. Radiother Oncol 2004;71:275-80.
10. Monnier L, Touboul E, Durdux C, Lang P, St Guily JL, Huguet F. Hypofractionated palliative radiotherapy for advanced head and neck cancer: the IHF2SQ regimen. Head Neck 2013;35:1683-8.
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11. Porceddu SV, Rosser B, Burmeister BH, et al. Hypofractionated radiotherapy for the palliation of advanced head and neck cancer in patients unsuitable for curative treatment--"Hypo Trial". Radiother Oncol 2007;85:456-62.
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12. Mendenhall WM, Amdur RJ, Palta JR. Intensity-Modulated Radiotherapy in the Standard Management of Head and Neck Cancer: Promises and Pitfalls. Journal of Clinical Oncology 2006;24:2618-23.
13. Groenvold M, Petersen MA, Aaronson NK, et al. The development of the EORTC QLQ-C15-PAL: a shortened questionnaire for cancer patients in palliative care. Eur J Cancer 2006;42:55-64.
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14. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
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Journal of the National Cancer Institute 1993;85:365-76.
15. National Cancer Institute, Common Terminology Criteria for Adverse Events v4.0 NCI, NIH, DHHS May 29, 2009 2009;NIH publication # 09-7473.
16. Kaplan EL, Meier P. Nonparametric Estimation from Incomplete Observations. Journal of the American Statistical Association 1958;53:457-81.
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17. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Annals of surgical oncology 2010;17:1471-4. 18. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Controlled clinical
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trials 1996;17:343-6.
19. Khan L, Tjong M, Raziee H, et al. Role of stereotactic body radiotherapy for symptom control in head
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and neck cancer patients. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 2015;23:1099-103.
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Figure Legends
Figure 1a: Overall Survival
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Legend, figure 1a: Overall. Survival, in months, from the time of enrollment with numbers at risk. Median overall survival was 6.5 months
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Figure 1b: Progression-Free Survival.
Legend, figure 1b: Progression-free survival, in months, from the time of enrollment with
Figure 2: Patient reported outcomes
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numbers at risk. Median progression-free survival was 3.2 months.
Figure 2 legend: Proportion of patients with same or better scores vs worse scores than their baseline values in their quality of life and physical functioning scores, and proportion of patients
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with same or less problems vs more problems than their baseline values in their symptom
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scores according to the duration of follow-up in months.
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Palliative radiotherapy for advanced head and neck carcinomas, a phase II study.
Tables Table 1, patients’ characteristics
N
Histology
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Pre-existing dysphagia
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Pre-treatment feeding tube Pre-treatment tracheostomy KPS
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Oral cavity Salivary gland Larynx Nasopharynx Oropharynx Paranasal sinuses Other T0-Tx T1 T2 T3 T4 N0-Nx N1 N2 N3 M0-Mx M1 Salivary Squamous None Liquids Solids Total
Female 5 (16%) : Male 27 (84%) Median 74, range 44-90 y.o Median 72, range 19 – 311 cc 4 (13%) 2 (6%) 4 (13%) 1 (3%) 9 (28%) 3 (9%) 9 (28%)
60 70 80 90
7 (23%) 2 (7%) 2 (7%) 6 (20%) 13 (43%) 10 (33%) 1 (3%) 10 (33%) 9 (30%) 23 (74%) 8 (26%) 2 (6%) 29 (94%) 19 (61%) 1 (3%) 10 (32%) 1 (3%) 3 (9%)
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Gender Age GTV volume (cc) Primary
3 (9%) 1 (4%) 10 (36%) 13 (46%) 4 (14%)
Legend, Table 1: Patients’ characteristics. GTV is Gross Tumour Volume, the tumoral volume included in the radiation plan.
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Table 2, Motives for palliative treatment, n=32
1 massive meningeal involvement 1 T3 palate but lung transplant, severe cardiac disease, poor lung function 1 massive pterygoid muscle involvement with cardiac disease precluding chemotherapy or surgery 1 oral cavity with massive bony involvement, 81 y.o., 40 pounds weight loss, poor ECOG 8 metastatic HNSCC (stage IVc) 1 stage IV colon cancer 4 concomitant stage III-IV lung cancer 1 acute lymphoid leukemia, 83 y.o. Median age 80 (range 44-90) 86% stage IVa-b 10 with significant cardio-vascular or kidney disease
RI PT
3
incurable despite fit patient radically treatable lesions but significant comorbid conditions
SC
1
14 patients with distant disease
AC C
EP
TE D
M AN U
14 patient refusal of radical treatment
Pall iat ive RT for ad va nced H &N ca ncer
tables
ACCEPTED MANUSCRIPT
Worst toxicity After 2 month (n=21)
3 2 (7) 2 (7) 4 (13) -
SC
Worst toxicity After 1 month (n=23)
Skin Mucosal Laryngeal Hemorrhage Other Overall Skin Mucosal Laryngeal Hemorrhage Other Overall Skin Mucosal Laryngeal Hemorrhage Other Overall
Grade, n (%) 1 2 15 (50) 4 (13) 10 (33) 2 (7) 2 (7) 3 (10) 2 (7) 6 (20) 6 (20) 10 (33) 11 (37) 6 (30) 1 (5) 3 (14) 1 (5) 1 (5) 1 (5) 1 (5) 4 (19) 4 (19) 8 (38) 5 (24) 5 (27) 1 (6) 2 (11) 1 (6) 1 (6) 1 (6) 1 (6) 3 (17) 3 (17) 6 (33) 4 (22)
M AN U
Worst toxicity (n=31)
0 11 (37) 16 (53) 28 (93) 25 (83) 16 (53) 5 (17) 13 (65) 17 (81) 19 (95) 18 (90) 13 (62) 8 (38) 12 (67) 15 (83) 17 (94) 16 (89) 12 (67) 8 (44)
RI PT
Table 3, toxicities
Legend, table 3: worst treatment related reported toxicity as graded with the CTCAE v4.0 during
AC C
EP
TE D
the whole follow-up period and at 1 and 2 months after radiotherapy.
Pall iat ive RT for ad va nced H &N ca ncer
tables
ACCEPTED MANUSCRIPT
Overall Survival 1.0 Censored
95% Confidence Limits
RI PT
0.6
0.4
SC
Survival
0.8
0.0 At Risk
32
9
0
10
M AN U
0.2
2
1
0
20
30
40
AC C
EP
TE D
months
ACCEPTED MANUSCRIPT
Progression Free Survival 1.0 Censored
95% Confidence Limits
RI PT
0.6
0.4
SC
Survival
0.8
0.0 At Risk
32
7
1
0
5
10
M AN U
0.2
1
1
15
20
AC C
EP
TE D
months
30
40
ACCEPTED MANUSCRIPT Global Quality of Life
Physical Func oning
90%
90%
80%
76% 67% 59%
60%
58%
50%
40%
42%
41%
38%
33%
35% 30%
24%
20%
62%
same or be er
73%
60% 50% 35% 29%
25%
27%
20%
25%
Head and Neck Pain
TE D
worse
90%
83%
80% 77%
71%
70%
73%
EP
70%
65%
60% 50% 40%
0%
30%
23%
AC C
10%
76%
71%
58%
58%
50%
42%
42%
40% 30%
29% 25%
24%
20%
13%
0%
same or be er
20%
60%
87%
10%
0%
30%
70%
75%
M AN U
Percentage of respondents
71%
10%
Percentage of respondents
80%
75%
Percentage of respondents
75%
29%
worse
Fa gue
90%
30%
24%
20%
Swallowing Problems
40%
25%
worse
90%
71%
42% 27%
30%
0%
65%
29%
same or be er
worse
58%
41%
38%
40%
0%
70%
59%
50%
10%
80%
73%
60%
10%
same or be er
76%
SC
65%
62%
75% 70%
RI PT
70%
Percentage of respondents
Percentage of respondents
80%
35%
27% 17%
same or be er
worse