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Table of Contents
ORIGINAL ARTICLE: GERIATRIC ONCOLOGY SECTION
Year : 2020  |  Volume : 3  |  Issue : 3  |  Page : 482-488

Safety and efficacy of concurrent chemoradiotherapy for head-and-neck cancers in older versus younger patients: Post hoc analysis of a randomized controlled trial


Department of Medical Oncology, Tata Memorial Hospital, Maharashtra, Homi Bhabha National Institute, Mumbai, India

Date of Submission20-May-2020
Date of Decision14-Jun-2020
Date of Acceptance27-Jul-2020
Date of Web Publication19-Sep-2020

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_208_20

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  Abstract 


Background: Head-and- neck squamous cell carcinoma (HNSCC) is a commonly occurring malignancy in the geriatric population. However, there is a scarcity of data regarding the efficacy and safety of concurrent chemoradiotherapy (CRT) in these patients.
Objectives: We performed a post hoc analysis of a randomized study conducted at our institution to compare the outcomes and toxicities of concurrent CRT in older versus younger patients with HNSCC.
Materials and Methods: The present analysis is based on a study conducted at Tata Memorial Hospital, Mumbai, India, on patients with locally advanced HNSCC, planned for radical concurrent CRT. The patients were randomized to receive cisplatin either once-a-week at a dose of 30 mg/m2 or once-in-3-weeks at a dose of 100 mg/m2. The database of this study was used for the post hoc analysis. We evaluated the differences in the demographic and clinical features, grade 3 or worse adverse events, compliance to treatment, locoregional control (LRC), progression-free survival (PFS), and overall survival (OS) between the older (aged ≥ 60 years) and the younger patients.
Results: Out of 300 patients, 283 (94.3%) comprised the younger cohort (age <60 years) and 17 (5.7%) comprised the older cohort. There was no difference in the occurrence of severe (grade 3/4) toxicities between the two groups. At a median follow-up of 22 months (range, 3–51 months), the cumulative LRC at 2 years was 67.1% and 100% for the younger and older groups, respectively (P = 0.018). The estimated median PFS in younger patients was 24.4 months (95% confidence interval, 12.5–36.3), while it was not reached in the older group (P = 0.53). The estimated median OS was 41.3 months in the younger patients but was not reached in the older group (P = 0.613).
Conclusions: Cisplatin-based concurrent CRT appears to be as efficacious in carefully selected fit older patients as in younger patients; moreover, toxicities appear to be similar in both the groups.

Keywords: Chemoradiotherapy, geriatric, head-and-neck squamous cell carcinoma, older


How to cite this article:
Singh GK, Noronha V, Patil VM, Menon N, Joshi A, Prabhash K. Safety and efficacy of concurrent chemoradiotherapy for head-and-neck cancers in older versus younger patients: Post hoc analysis of a randomized controlled trial. Cancer Res Stat Treat 2020;3:482-8

How to cite this URL:
Singh GK, Noronha V, Patil VM, Menon N, Joshi A, Prabhash K. Safety and efficacy of concurrent chemoradiotherapy for head-and-neck cancers in older versus younger patients: Post hoc analysis of a randomized controlled trial. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Oct 30];3:482-8. Available from: https://www.crstonline.com/text.asp?2020/3/3/482/295542




  Introduction Top


Head-and-neck squamous cell carcinoma (HNSCC) is the fifth most common cancer in the world; however, in India, it is the most common malignancy.[1],[2] There is an increasing incidence of HNSCC among older patients (aged >70 years), who comprise 25% of the total cases of HNSCC.[3] In the Indian subcontinent, the geriatric age group comprises 10% of all patients with HNSCC.[4] The two reasons proposed for the above-mentioned incidence are an increase in the average life expectancy worldwide and a higher risk of cancer development with increasing age.[5],[6] According to Vigneswaran et al., the average age for the diagnosis of smoking-associated and smokeless tobacco-associated HNSCC is 60 and 78 years, respectively.[7] There is no common consensus on the definition and age limit for the geriatric population. As per the United States National Institute of Aging, 65 years is usually taken as the cutoff in the Western countries.[8] However, for developing countries like India, the cutoff is lower because of the lower life expectancy and poorer health infrastructure.[9],[10] It is noteworthy that the chronological age can differ from the physiological age, depending on the performance status and the presence of comorbidities.[1]

Radical chemoradiotherapy (CRT) comprising a radiation dose of 66–70 Gy concurrently with cisplatin at a dose of 100 mg/m2 delivered once-in-3-weeks is considered the preferred nonsurgical treatment approach for locally advanced HNSCC (LA-HNSCC).[11],[12] In patients undergoing or those who have undergone curative intent surgery and are noted to have high-risk features, such as close or positive margins or extracapsular nodal extension, adjuvant CRT is the standard of care.[13],[14] CRT has resulted in a significant improvement in the survival as compared to conventional radiotherapy alone in patients with LA-HNSCC.[15]

The likelihood of administration of radical treatment to the geriatric age group is lower than that in younger patients, due to the fear of severe toxicities.[2],[10] Hence, in patients with an equal comorbidity index, age remains the independent deciding factor for the administration of inferior, less intensive treatment.[16] In addition, the quality of life (QOL) is of utmost importance and takes priority during the treatment of older patients.[2] As a result, older patients are usually excluded from enrollment in clinical trials.[17] Thus, the dearth of data on cancer management in the geriatric age group invites hesitancy in the clinical decision-making. To address this unmet need, we conducted this post hoc analysis to compare the efficacy and adverse events of concurrent CRT between older and younger patients with LA-HNSCC.


  Materials and Methods Top


General study details

This is a retrospective, posthoc analysis of a trial conducted in the Department of Medical Oncology and the Head and Neck Disease Management Group of the Tata Memorial Hospital in Mumbai, India. We had earlier published the outcomes and adverse events of the Phase III randomized controlled trial on 300 patients with LA-HNSCC of the oral cavity, pharynx, and larynx [Supplementary Appendix 1]. The aim was to compare once-a-week cisplatin (OWC) to once-in-3-weeks cisplatin (O3WC) in combination with radiation. Patients were randomized 1:1 to receive either radiotherapy (60–70 Gy) with concurrent OWC at a dose of 30 mg/m2 or O3WC at a dose of 100 mg/m2, after obtaining their written informed consent. Locoregional control (LRC) was the primary end point of the study; progression-free survival (PFS), overall survival (OS), adverse events, treatment compliance, and response rate were the secondary end points.[11] The trial was approved by the institutional ethics committee (Tata Memorial Hospital Human Ethics Committee-I, Project Number 937; Date of Approval: January 19, 2011). It was registered with the Clinical Trials Registry of India (CTRI/2012/10/003062). The study was monitored by the data safety and monitoring subcommittee. The trial was carried out in accordance with the guidelines issued by the 18th Helsinki World Medical Assembly (1964) and its amendments. There was no funding used for the current analysis.

Participants

The original phase III trial included patients with LA-HNSCC, Stage III or IV with no distant metastases, originating in the oral cavity, larynx, oropharynx or hypopharynx. Patients included were those planned for radical concurrent CRT, either in the definitive setting (for patients with unresectable disease or patients planned for organ preservation) or in the adjuvant setting (for patients with one or more high-risk features including close or positive margins, extracapsular extension, involvement of more than two lymph nodes [LNs], T4 primary). Patients had to have a performance status of 0 to 2 and adequate organ functions. The detailed inclusion and exclusion criteria are available in the protocol [Supplementary Appendix 1] and in the original publication.[11]

Variables

The primary end point of our study was to compare the LRC between older and younger patients. LRC was defined as the lack of disease recurrence at the primary tumor site or regional LNs two years after CRT. Secondary end points of our study were comparison of PFS, OS, toxicities (grade 3 and above), and compliance with treatment between the older and younger patients. PFS was defined as the time from randomization to any of the following events: first evidence of any relapse (locoregional or distant), development of a second primary tumor, and death from any cause were considered as events. OS was calculated from the date of randomization to the date of death from any cause.

Study methodology

Demographic, toxicity, and outcome data were extracted from the above-mentioned data set. The trial data were entered in the patient files and the case report forms. The patients were divided into two groups on the basis of age – younger (<60 years) and older (≥60 years). Patients aged up to 70 years were included in this analysis. Toxicity scoring was done according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.03). Grade 3 and 4 toxicities were recorded to determine the difference in the occurrence of severe toxicities between the groups [Figure 1].
Figure 1: Flowchart for patient selection and evaluation process

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Statistics

All statistical analyses were done with the Statistical Package for the Social Sciences (SPSS) (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp), and a P < 0.05 was considered statistically significant. The survival outcomes were estimated using the Kaplan–Meier method, and log-rank test was used to detect any differences between the two groups.[18] Cox proportional hazards model was used to compare survival with age group as a covariate.[19],[20] Complications, grade 3 or higher adverse events, and compliance were evaluated. These were compared between the two groups using the Chi-square test. Toxicities were graded according to the CTCAE.


  Results Top


Baseline characteristics

The detailed baseline characteristics of the patients have already been published.[11] The median age of the patients was 41.5 years (range, 26–65) and 47 years (range, 25–67) in the OWC and O3WC arm, respectively. Out of 300 patients, 17 were in the older group, with a median age of 61 years (range, 60–67), and 283 patients were in the younger group, with a median age of 43 years (range, 25–59 years). The majority of the patients in both the groups had stage IVA disease. The younger cohort had disproportionately more oral cavity primaries; the difference in the site of the primary tumor was statistically significant between the two arms (P < 0.001). Further detailed baseline characteristics are mentioned in [Table 1].
Table 1: Baseline characteristics and treatment comparison between younger and older patients

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Comparison of outcomes between older and younger patients

The median follow-up period of our study was 22 (range, 3–51) months. Locoregional failure was observed in 93 patients in the younger group (n = 283) versus none in the older group (n = 17); the cumulative LRC at 2 years was 67.1% in the younger and 100% in the older group (P = 0.018) [Figure 2]. At the time of censoring, there were 134 (n = 283) and 11 (n = 17) events in the younger and older patients, respectively; the estimated median PFS for the younger cohort was 24.4 months (95% confidence interval, 12.5–36.3), and it was not reached in the older cohort (P = 0.53) [Figure 3]. At the time of censoring, there were 106 (n = 283) and 7 (n = 17) deaths in the younger and older groups, respectively, and the estimated median OS was 41.3 months in the younger group and not reached in the older group (P = 0.613)[Figure 4].
Figure 2: Kaplan–Meier curve showing locoregional control in younger and older patients

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Figure 3: Kaplan–Meier curve showing progression-free survival in (PFS) younger and older patients

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Figure 4: Kaplan–Meier curve showing overall survival in (LRC) younger and older patients

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Comparison of adverse events between younger and older patients

[Table 2] gives the detailed comparison of the grade 3 and 4 treatment-related toxicities. Overall, the incidence of these toxicities was similar in both the arms. The rates of leukopenia (17.6% versus 8.9%) and neutropenia (17.6% versus 6.4%) were higher in the older patients; however, the differences were not statistically significant. In addition, there was a nonsignificant increase in the incidence of nonhematological toxicities, such as vomiting (4.3% vs. 0%), diarrhea (3.6% vs. 0%), and odynophagia (48.2% vs. 28.5%) in the younger group. Notably, despite a similar cisplatin dose and schedule, no difference in all grade 3/4 adverse events and other complications such as rate of delay in chemotherapy, rate of hospitalization, and deaths due to toxicities was noted. The rate of dose reductions was higher in the older patients than in the younger ones (17.6% vs. 8.1%) (P = 0.22) [Table 3].
Table 2: Comparison of toxicities between younger and older patients

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Table 3: Treatment complications comparison between younger and older patients

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  Discussion Top


There are no standard guidelines or recommendations to help decide the appropriate treatment protocol for HNSCC in the older patients. Hence, we performed a post hoc analysis of our Phase III randomized controlled trial to determine the efficacy and safety of concurrent CRT in these patients. We observed that CRT resulted in significantly better LRC (P = 0.018) in older patients, while the PFS, OS, and adverse events were similar for both the groups after a median follow-up of 22 months.

However, our results may be hypothesis-generating rather than definitive, due to the small number of patients included in the older group (≥60 years). Older patients are usually not given radical treatment and hence are not enrolled in clinical trials. Historically, the number of older patients included in the pivotal trials has been small. In the intergroup study by Adelstein et al., the mean age of the patients in the CRT arm was 56.8 years (range, 25–80), while in the EORTC 22931 study, age >70 years was an exclusion criterion. Similarly, in the intergroup 9501 study, only 11 patients (5%) who received CRT were aged >70 years.[13],[14],[21]

Although the older patients were noted to have a significantly better LRC, the significance of this observation is unclear because of the small sample size of the cohort and the fact that the analysis was not a preplanned analysis. Nevertheless, we can conclude that cisplatin-based CRT is efficacious in the older patients. With regard to the survival outcomes, we did not observe any difference in the PFS and OS of older and younger patients. A number of studies conducted previously have shown similar results with respect to PFS and OS. In an analysis comparing the results of definite CRT with radiotherapy alone in 4042 older (>70 years of age) patients with HNSCC, Amini et al. noted a significant improvement in the OS from CRT.[22] Müller von der Grün et al. retrospectively studied 158 patients who received definitive CRT for HNSCC. They found that 58 patients belonged to the older cohort (>65 years). The results of the various outcomes such as OS, PFS, disease control rate, and distant metastasis-free survival were not different between the older and younger groups after a median follow-up period of 29 months.[23] Contrastingly, the MACH-NC and MARCH meta-analysis suggested that the patients aged >70 years did not benefit from CRT. However, the use of older nonconformal radiotherapy techniques in the analysis makes these findings difficult to interpret in the current era.[24],[25]

Although O3WC (100 mg/m2) is the standard chemotherapy regimen in the concurrent setting, various other regimens have also been tried and practiced. In our study, we found that OWC (30 mg/m2) was not noninferior to O3WC (100 mg/m2).[11] However, it is evident in our analysis that both the once-a-week and the once-in-3-weeks protocols were safe and well tolerated in geriatric patients. We also analyzed the toxicity profile and found that around 64.3% of the older patients needed feeding tube insertion while on treatment, and dysphagia was the most common nonhematological grade 3 or higher toxicity recorded. Only 17.6% of the older patients were hospitalized while receiving treatment in our study and there was no treatment-related mortality. We found that less than 30% of older patients received the weekly cisplatin regimen, and despite this, the toxicity profile was not significantly different from that of the younger cohort. Müller von der Grün et al. also noted that the older patients did not develop severe acute toxicities.[23]

However, there are other studies in which the authors have reported acute toxicities in some cases. Haehl et al. found a relatively high rate of acute toxicity in their study, where 56.1% of the patients in the older age group developed CTCAE grade 3 or 4 toxicities.[3] In a retrospective analysis by Maggiore et al., dysphagia was the most common toxicity observed requiring gastrostomy feeding tube insertion.[26] A recent Surveillance, Epidemiology, and End Results Medicare study carried out from 2000 to 2009 showed that patients aged ≥66 years either had to visit the emergency room (62%) or required hospitalization while receiving CRT/radiotherapy alone (46%). In addition, gastrointestinal and hematologic toxicities were three times higher in the CRT arm.[27]

Few Indian studies have also been conducted covering this research area and have reported similar outcomes. Srinivasalu et al. and Manir et al. observed similar survival outcomes in older and younger patients.[1],[6] Srinivasalu et al. also drew similar conclusions regarding the use of O3WC (100 mg/m2) and OWC (40 mg/m2) protocols and found them to be equally safe in older patients.[1] [Table 4] enumerates different chemotherapeutic agents and regimens used in various studies of CRT in older patients, showing comparable data on adverse events.[1],[3],[6],[23]
Table 4: Comparison of age cutoff, chemotherapeutic agents, and toxicities in the older patients

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Our analysis showed that CRT is well tolerated in older patients akin to their younger counterparts, which underlines the fact that age should not be considered a factor to deny optimal treatment to patients with LA-HNSCC. This suggestion is supported by a relatively large number of studies that similarly recommend the use of CRT. The authors of the largest published database analysis of 4165 patients concluded that chemotherapy should be an option regardless of the age group.[28] Some non-comparative retrospective studies have also concluded that CRT should be considered in older patients; however, they also warn of the potential of higher toxicity.[29],[30] Similarly, a recent analysis by Juarez et al. also proposed that radiotherapy and CRT-like nonsurgical methods are more commonly employed in older patients stressing on the importance of considering and adopting these modalities.[31]

Our analysis compares the outcomes and safety of CRT between younger and older patients with LA-HNSCC. The original study was a prospective randomized trial; however, the subset analysis based on age was an unplanned post hoc analysis. CRT was found to be effective and safe in the older population and can be used as the preferred treatment option in fit patients. However, there are a few limitations of our study; first, we did not use any assessment tools such as the geriatric assessment, which could have given a better idea of the functional age and wellness of the older patients.[32] Second, further subdivision of the older patients could have provided a more detailed tolerance picture. Third, the inclusion criteria had an upper age limit of 70 years, and therefore, the number of geriatric patients who were actually included was very small. Finally, we did not evaluate the QOL data in our study, which further limits the study.


  Conclusion Top


Since the number of older patients was small in this unplanned subset analysis, the only possible conclusion is that cisplatin-based concurrent CRT does not appear to be less efficacious in carefully selected fit older patients than in younger patients and leads to similar toxicities.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Supplementary Appendix Top


Supplementary Appendix 1: Trial Protocol:

Phase III noninferiority randomized trial comparing 3-weekly cisplatin versus weekly cisplatin in combination with radiation therapy in patients with advanced carcinoma of the head and neck


Author(s): Vanita Noronha/Kumar Prabhash/Sarbani Ghosh-Laskar

Document type: Clinical research protocol

Development Phase: III

Financial Disclosure: None

Version: 4

Date: November 10, 2014

Previous Version and Date: Version 3.0 dated October 10, 2013


  Introduction Top


Head-and-neck cancer accounts for 8% of cancers worldwide, but up to one-third of all cancers in India. The majority of patients present with locoregionally advanced disease. For patients with advanced, i.e., stage III or IV, disease, the standard of care is surgery, if the disease is resectable, followed by adjuvant concurrent chemoradiotherapy (CRT)[1],[2] or definitive concurrent CRT for unresectable or inoperable disease.[3] The MACH-NC update reported an absolute survival benefit of 6.5% at 5 years when chemotherapy was administered concurrently with radiotherapy (RT).[4] The standard chemotherapy regimen used along with RT is cisplatin 100 mg/m2 given intravenously every 21 days, i.e., on days 1, 22, and 43 of RT.

The high-dose 3-weekly cisplatin regimen requires intensive supportive care and often requires admission, with the use of inpatient resources. This is very challenging in our setup. High-dose 3-weekly cisplatin CRT causes marked toxicities, and as a result, many patients cannot receive all of the planned three doses of cisplatin chemotherapy. 77% of the patients treated with concurrent CRT in the postoperative setting, on the RTOG 9501 protocol, experienced > grade 3 acute toxicity.[2] Even in the setting of definitive chemoradiation, toxicity is excessive, with 85% of patients experiencing grade 3–5 toxicities; specifically, 43% of patients experience grade 3–5 mucositis/dysphagia, 40% experience grade 3–5 leukopenia, and 7% experience grade 3–5 skin toxicity, and the rate of toxic deaths is 4%.[3] Compliance with chemotherapy decreases with the number of chemotherapy courses delivered. In the EORTC 22931 trial by Bernier et al. (postoperative CRT), 11% of patients stopped chemotherapy after only one course was delivered, 15% of the patients stopped chemotherapy after two courses, and only 49% of patients received cycle 3 on time, without delay.[1] Thus, over half of the patients do not receive all the planned three doses of chemotherapy and dose intensity is compromised. Dose intensity has been proven to be important to increase efficacy in other malignancies such as breast cancer[5] and ovarian cancer[6] and is likely to be important for efficacy in head-and-neck cancer as well. Dose intensity when given in high-dose 3-weekly schedule was 24 mg/m2/week.[1],[2],[3]

The initial half-life of cisplatin is 20–30 min, with a beta half-life of 60 min, a terminal half-life of ~24 h, and a secondary half-life of 44–73 h.[7] Thus, administering cisplatin more often may be beneficial in enhancing efficacy. However, at a dose of 100 mg/m2, the toxicity is significant and administering doses more frequently than 3 weekly is impossible. Hence, we hypothesize that administering cisplatin at a lower dose, like 30 mg/m2, but at more frequent intervals, i.e., weekly, will permit dose-dense administration, thereby improving efficacy.

The administration of low-dose cisplatin weekly has been widely adopted. In our standard practice, we prescribe cisplatin 30 mg/m2 week ly along with concurrent RT. Many centers, including our own at Tata Memorial Hospital,[8] have published retrospective as well as prospective analyses of their experience using a weekly cisplatin regimen concurrently with RT.[9],[10],[11],[12],[13],[14],[15],[16],[17] The RTOG also uses weekly cisplatin along with radiation, in their protocols which utilize CRT.[18] In spite of widespread use of this regimen, there has never been a prospective randomized trial comparing the published standard of care, i.e., high-dose 3-weekly cisplatin with low-dose weekly cisplatin, in combination with radiation in the curative setting in advanced head-and-neck cancer.

Aims and objective

This was Phase III randomized open-label noninferiority trial comparing cisplatin 30 mg/m2 intravenous (IV) weekly to cisplatin 100 mg/m2 IV 3 weekly, in combination with radiation therapy, in patients with locally advanced head-and-neck squamous cell carcinoma (SCC) or undifferentiated carcinoma, either in the adjuvant setting after definitive surgery, or as definitive therapy in patients with unresectable or inoperable disease, in terms of efficacy (response rate, locoregional control, progression-free survival [PFS], overall survival [OS]), compliance to therapy, toxicity, and quality of life (QOL).

Outcomes

  • Primary: Locoregional control
  • Secondary: Response rate, toxicity, compliance to treatment, PFS, OS, and QOL
  • Exploratory: Regimen-related differences in PK/PD of cisplatin.



  Investigation Plan Top


Study design

This was Phase III randomized open-label noninferiority trial.

Study population

Patients with Stage III or IV SCC or undifferentiated carcinoma of the head-and-neck region, originating in the

  • Oral cavity
  • Oropharynx
  • Hypopharynx
  • Larynx
  • Unknown primary, with cervical lymphadenopathy with no clinical evidence of metastatic disease.


In the adjuvant setting, patients who will be advised adjuvant CRT will be patients who have high-risk features for recurrence, including:

  • Close or positive margins
  • Perinodal extension
  • >2 LNs positive
  • T4 primary.


A screen log will be maintained, with the reasons for screen failure.

Inclusion criteria

  1. Age <70 years
  2. Histological- or cytological-proven diagnosis of SCC or undifferentiated carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx or SCC of the head-and-neck region of unknown primary
  3. Disease is stage III or IV, with no evidence of distant metastases
  4. ECOG performance status ≤2
  5. Patients who are candidates for adjuvant concurrent CRT, i.e., tumor histopathology, demonstrate close or positive margins, perinodal extension, >2 LNs positive, or T4 primary
  6. Patients with no contraindications to cisplatin chemotherapy
  7. Patients with no contraindications to RT
  8. Patients who can give informed consent to participate in the study
  9. Patients who can be followed up and can take all the cycles of chemotherapy at the participating institution
  10. Adequate organ function


    • Hematological – Hemoglobin >90 g/L, ANC ≥1.5 × 109/L, platelets ≥ 100 × 109/L
    • Liver functions – Bilirubin ≤2× upper limit of normal (ULN), AST/ALT/ALP ≤2.5 × ULN, serum albumin ≥ 30 g/L
    • Renal function – Creatinine ≤1.5 ULN, creatinine clearance >50 mL/min.


  11. Women of child-bearing age should have a negative pregnancy test at the time of randomization and should be willing to use adequate contraception during the treatment phase of the trial.


Exclusion criteria

  1. Baseline sensorineural hearing loss, which is moderate or severe
  2. Calculated GFR <50 cc/min
  3. Patients who have received any neoadjuvant/induction chemotherapy
  4. Serious comorbidities such as severe cardiac failure or severe pulmonary compromise or severe and active infections
  5. Presence of distant metastatic disease
  6. Life expectancy less than 6 months
  7. Patients with active second malignancies, apart from skin cancers and cervical intraepithelial neoplasia
  8. Patients on other investigational drugs within last 30 days.


Treatment

Treatment drug

Cisplatin is a platinum metal chemotherapeutic agent that is routinely used in combination with radiation therapy for the treatment of head-and-neck cancer. Its mechanism of action is via the formation of DNA adducts, resulting in inhibition of DNA synthesis, inhibition of transcription, and cell-killing. Cisplatin is a radiosensitizer and hence acts synergistically with radiation therapy. Cisplatin is diluted in normal saline and administered over 1 h.[7]

Cisplatin is highly emetogenic and causes both immediate chemotherapy-induced nausea and vomiting and delayed emesis. We will administer routine premedications before cisplatin, including oral aprepitant (for delayed emesis), IV granisetron, IV dexamethasone, and IV ranitidine. To prevent nephrotoxicity, we will administer prehydration with 500 cc of normal saline and posthydration with an additional 500 cc of normal saline. To prevent dyselectrolytemia, we will give infusion of potassium and magnesium.

Radiotherapy

Pretreatment dental care

Before patients start their radiation therapy, dental assessment is required. Dental care should be provided before initiating RT, to avoid any unnecessary interruption of irradiation. This should include scaling, application of fluoride gel, and attention to carious teeth or any otherr dental procedure that may be needed.

Nutritional support

Nutritional care is crucial during the radiation treatment. Patients should receive dietary advice to help maintain their weight and nitrogen balance during the course of RT.

If weight reduction exceeds 8%, a feeding tube is recommended. A pretreatment feeding tube may be inserted if thought necessary by the treating oncologist.

Patient positioning and immobilization

In supine treatment position, patients are immobilized using a thermoplastic mask.

Techniques

Irradiation can be planned using either standard two-dimensional (2D) technique or 3D conformal technique or IMRT.

The selection of technique is at the discretion of the treating oncologist.


  Simulation Top


The lateral projection of the primary tumor and nodal disease is marked on simulation films, by reconstructing the information available from clinical examination and computed tomography (CT)/magnetic resonance imaging (MRI) scans.

To achieve maximum sparing of normal tissues, fields should be shaped with custom blocks or multi-leaf collimators. Skin fall-off should be avoided anteriorly whenever possible.

No surface bolus should be used except in case of skin infiltration.

For 2D/2.5D RT, simulation films for all treatment portals should be taken. For 3DCRT/IMRT treatments, at least two orthogonal port films should be taken before treatment

Information relevant to 3DCRT/IMRT planning specifically is described below.

Treatment volumes and radiation doses (for three-dimensional planning)

With patient in the treatment position, 3 mm CT cuts will be obtained with IV contrast, from vertex to at least 10 cm below the suprasternal notch.


  Definition of Volumes Top


The definition of volumes will be in accordance with the 1993 ICRU Report #50.


  Gross Target Volumes Top


Gross target volume is defined as all known gross disease determined from clinical and imaging information and endoscopic findings.


  Clinical Target Volume Top


Clinical target volume (CTV) comprises the gross primary tumor, the involved positive LN areas as defined clinically and radiologically, and the potential subclinical or microscopic involvement.

The CTV is further defined as a low-risk CTV1 and a high-risk CTV2, to stratify the doses according to risk levels.


  Clinical Target Volume 1 (Low-Risk, Prophylactic) Top


The CTV1 represents the nodal region to receive elective irradiation, i.e., potential subclinical disease. This will include uninvolved neck nodes at low risk, at least the first two echelons of LN, beyond those involved.

For elective neck irradiation in N0 patients, at least the first two echelons of LN will be included.


  Clinical Target Volume 2 (High-Risk, Therapeutic) Top


The CTV2 represents the primary tumor with a margin of about 0.5–2 cm and the involved nodal region to receive the prescription dose. This represents the macroscopic disease which is identified clinically or radiologically.


  Bilateral Neck Irradiation Top


Contralateral neck irradiation should be considered in the following situations:

  • The presence of positive LN ≥3 cm in the ipsilateral neck
  • The risk of occult or subclinical nodal metastases is ≥20% even if ipsilateral neck is negative. Appendix [Table 1] provides a guide on primary tumors (location and T stage), where such risk of occult or subclinical nodal metastases is intermediate or high.



  Delineation of Nodal Clinical Target Volume Top


A complete atlas of contrast-enhanced CT sections depicting guideline CTVs that encompass the various node levels from the base of skull to the level of the sternoclavicular joints can be found on the following websites:




  Positive Neck Nodes Top


The treatment of selected neck levels (e.g., levels I–III or II–IV) is advocated for the node-negative side of the neck and in patients with a single small node (e.g., N1).



For all other neck stages (e.g., N2 disease), comprehensive treatment of all levels with or without inclusion of level VI or retropharyngeal nodes is recommended.

In case of involvement of upper level II (Iia or Iib), it is recommended to extend the upper border to include the retrostyloid space up to the base of skull.

In case of involvement of level IV or Vb with one or more LNs, it is recommended to include the supraclavicular fossa in the CTV.

It is recommended to include the adjacent muscle in the CTV, when an involved LN abuts a muscle and/or shows clear radiological evidence of muscle infiltration, at least for the entire invaded level and at least with a 1 cm margin in all directions.

When an involved LN is located at the boundary with another level, which was not intended to be part of the CTV, it is recommended to extend the CTV to include this adjacent level. This recommendation will only apply to patients with a single LN (N1), and for whom a selective treatment may be advocated, e. g., an oropharyngeal SCC with a N1 node in level II at the boundary with level Ib; an oral cavity tumor with a N1 node in level III at the boundary with level IV.


  Negative Neck Nodes Top


Recommendation for CTV delineation of various levels is based on the consensus guidelines proposed by the DAHANCA, EORTC, GORTEC, NCIC, and RTOG.[19]

At least two levels of nodal echelons should be treated.


  Planning Target Volume Top


The planning target volume (PTV) surrounds the CTV with a margin to compensate for set up uncertainties and potential organ motion. A minimum of 0.5–1 cm margin in all planes should be applied. The added margin will depend on the clinical practice at the institution.

When the CTV is immediately adjacent to the spinal cord or critical normal tissues, the PTV margin may be as small as 0.3 cm.

Two PTVs should be generated:

  • PTV1 to cover the CTV1
  • PTV2 to cover CTV2.


Organs at risk

These are the normal tissue structures whose radiation sensitivity may significantly influence the treatment planning and/or the prescribed dose.

In the head-and-neck region, organs at risk (OAR) are mainly spinal cord, larynx, parotid glands, upper esophageal sphincter, mandible, and brainstem. Whenever possible, unnecessary irradiation of the larynx should be avoided, e.g., a tumor of the oral cavity or of the oropharynx without extension inferiorly beyond the hyoid bone.

Doses



  • For 2DRT


    • Phase 1: 46 Gy/23 fractions, 2 Gy/#, one fraction per day
    • Phase 2: 24 Gy/12 fractions, 2 Gy/#, one fraction per day
    • Total dose to be 70 Gy/35 fractions/7 weeks for definitive chemoradiation.


  • For IMRT


    • Prescription dose should follow the ICRU 50 report.


PTV1:



PTV2:




  Treatment Planning Top


For 2D technique also, it will be preferable to acquire CT scans with the patient in the treatment position and using the same immobilization device as for treatment. Computerized plans with isodose distributions are required, at least at the following levels in 2D technique:

  • At the central axis of the field


Through the plane of where maximum tumor bulk is detected (if this does not coincide with the central axis; to confirm CTV and PTV coverage is adequate, the isodose distribution should be figured out, in this CT slice).

  • At the superior and inferior planes of all target volumes


For treatments utilizing tissue compensators, attempts should be made to provide dose distributions at the above levels.

The treatment planning has been described in detail for the IMRT technique (Section: Treatment volumes and radiation doses [for three-dimensional planning]).

For IMRT, isodose distributions are required in at least 10 equidistant CT slices:

  • Through the beam axes for the PTV
  • Through the plane of maximum tumor bulk
  • At the cranial and caudal planes of all target volumes
  • A sagittal slice and a coronal slice display isodoses 107%, 100%, 95%, 90%, 75%, 50%, and 25% isodoses.



  Imrt Planning Top


For details refer to the Section “Treatment volumes and radiation doses (for three-dimensional planning).”


  Dosimetry, Dose Homogeneity, and Constraint Top



  Dosimetry Top


For parallel-opposed fields, the prescription point is in the mid-plane of the central axis (ICRU 50); the use of tissue compensator is mandatory.

The cone-down plans must encompass the CTV2 within the prescription isodose curve.


  Dose Homogeneity Top


Missing tissue compensation should be used if available to provide sufficient levels of dose homogeneity within the PTV.

The prescribed dose should cover 95%–100% of the PTV.

The dose variation within the PTV (s) should not exceed + 7% and − 5% of the prescription point dose.

The maximum acceptable “hotspot” on the plan is 10%.

For electron fields, the dose will be specified as the peak dose (Dmax) with energy chosen to deliver at least 90% to areas at risk of recurrence.


  Dose Constraints Top



  Spinal Cord Top


The dose to the spinal cord should not exceed 40 Gy from the direct beams and 45 Gy from all dose contributions.

The maximum cord dose should not exceed 48 Gy to any volume larger than 2% of the whole spinal cord volume (approximately equivalent to 3 mm × 3 mm × 3 mm), e.g., if the location of areas at high risks of recurrence mandates a higher cord dose to achieve adequate coverage:

  • The dose to the brainstem should not exceed 50 Gy from all dose contributions
  • The total dose to the brachial plexus should not exceed 60 Gy.


Dose constraints to other OARs such as parotids and larynx are left at the discretion of the treating physician.


  Field Verification Top


Portal films should be taken weekly. At least one portal film for each field or at least two orthogonal films for 3DCRT/IMRT.


  Adjuvant Radiotherapy Top


For adjuvant RT, the principles of simulation, planning, and dose prescription will be the same.

The target volumes will consist of CTV1, CTV2, PTV1, and PTV2. The dose levels to these target volumes will be different. CTV1 and PTV1 will receive a dose of 54 Gy/30#, while CTV2 and PTV2 will receive 60 Gy/30#.

The doses to the OAR and quality assurance will remain the same.

Overall treatment time

Every attempt should be made to adhere to the prescribed overall treatment time. The prescribed overall treatment time is 6–7 weeks (40–47 days).



Radiation therapy interruption and missing doses

Planned radiation therapy interruptions are not permitted. Every effort should be made to keep treatment delays to a minimum. Treatment interruptions or delays will be permitted for grade 4 mucositis or other grade 3 and 4 treatment-related adverse events after consultation. Radiation therapy can be interrupted if necessary for 3–5 days and ideally should not exceed 5 treatment days at a time and 10 treatment days in total. Systemic therapy should also be withheld.

Compensation for not more than two missing doses should be permitted in 1 week. If treatment interruptions cannot be avoided, the reasons should be documented. As a guide, interrupted fractions should be replaced in one of the following ways:

  • If two doses are missed in 1 week, add a second fraction on a day of the same week, with a minimum of 6-h interval between the two fractions
  • In any case, no more than 6 fractions will be given in any particular week
  • Add the interrupted fractions at the end of treatment.


Compliance criteria

Every attempt should be ensured to adhere to the radiation therapy protocol guidelines.

Treatment breaks must be clearly indicated in the treatment records and in the CRF along with the reasons for the break. Treatment breaks, if necessary, should not exceed 5 treatment days at a time and 10 days in total. Treatment breaks should only be allowed for healing of severe adverse events, and/or intercurrent illness, and not for social or logistical reasons.

Plan normalization should provide at least coverage of 95% of the volume of the PTV. No more than 1% of the volume should receive less than 90% of the prescribed dose.

Deviations that fall out of the protocol definitions but are not considered to be major deviations will be considered as minor deviations. The deviations should be clearly noted in CRF pages. These deviations are not desirable and should be avoided but will be acceptable as minor deviations.

Appendix [Table 2] defines the main “per protocol” criteria. Major deviations are also clearly defined.

Dose modifications

Cisplatin will be administered at full dose on the scheduled date, provided

  1. Absolute neutrophil count >1000/mm3
  2. Platelet count >100,000/mm3
  3. Serum creatinine
  4. Creatinine clearance >50 mL/min, according to Cockcroft–Gault formula
  5. Serum bilirubin <2× ULN
  6. Serum AST and ALT <2.5 limit of normal
  7. If grade 3 mucositis occurs, the dose of cisplatin may be reduced by 20%
  8. If grade 2 neurotoxicity occurs, the dose of cisplatin may be reduced by 40%
  9. If grade 3 or higher neurotoxicity occurs, cisplatin will be omitted
  10. Cisplatin should not be substituted by carboplatin. If cisplatin cannot be administered, in spite of dose reduction, then chemotherapy will have to be held
  11. Cisplatin may be withheld if there is evidence of active infection
  12. Cisplatin may be omitted or dose reduced at physicians'/investigators' discretion, if investigator/physician feels that safety is a consideration.


If the above criteria are not met, the dose of cisplatin may be reduced or omitted as detailed in Appendix [Table 3], but RT will not be interrupted.



Treatment schema

This is a phase III randomized open-label noninferiority trial comparing cisplatin 30 mg/m2 weekly to cisplatin 100 mg/m2 3 weekly, in combination with radiation therapy, in patients with advanced head-and-neck SCC or undifferentiated carcinoma, either in the adjuvant setting after definitive surgery, or as definitive therapy in patients with unresectable or inoperable disease.

For all unresectable or inoperable patients, 6–8 weeks after the completion of definitive CRT, a repeat CT/MRI neck and paranasal sinuses and a repeat multidisciplinary team evaluation will be done. If there is evidence of residual disease, the patient will be evaluated for salvage surgery.

All patients will be followed up weekly for clinical evaluation during therapy and then every 3 months for the first 2 years [Appendix Table 4].








  Tumor Assessments Top


Patients planned for definitive treatment will undergo a baseline CT scan or MRI of the neck and paranasal sinuses and a baseline chest X-ray. However, patients under adjuvant settings will exempt from baseline CT scan or MRI. Additional imaging may be done, based on the investigator's discretion, if there are any abnormalities on examination or laboratory assessments. For patients treated with definitive chemoradiation, a follow-up CT scan or positron emission tomography/CT or MRI of the neck and paranasal sinuses will be done 6–8 weeks after the completion of therapy. Subsequent imaging will be done based on the investigator's discretion. Chest X-ray will be done annually. Tumor response will be assessed by the RECIST 1.1 criteria.


  Safety Assessments Top


Safety and tolerability will be assessed according to the NCI Common Terminology Criteria for Adverse Events version 4. All the adverse events will be documented, and appropriate action will be taken. Safety assessment will be done at each visit. In addition, we will assess weight loss, frequency of admission in each arm, need for extra IV hydration, swallowing status, and hearing loss.


  Quality of Life Assessment Top


QOL assessment will be done by the EORTC QLQ-Q30 and HN35 forms. QOL will be assessed at:

  • Baseline
  • Every 3 weeks during treatment
  • Completion of treatment
  • After completion of treatment, at every follow-up visit
  • At the end of the study visit.





  Nutritional Assessment Top


Nutritional evaluation will be done by the scored patient-generated subjective global assessment. Nutritional assessment will be performed at:

  • Baseline,
  • Every 3 weeks during treatment
  • Completion of treatment
  • After completion of treatment, at every follow-up visit
  • At the end of the study visit.



  Pk/pd Correlation Top


The PK/PD correlation study will be conducted in all patients. The purpose of this exploratory study is to evaluate the correlation between cisplatin levels and platinum-DNA adducts in the blood, the adducts in tumor, and the outcome of treatment. In addition to the treatment regimen, several other demographic factors may also affect the pharmacokinetics of cisplatin and the intratumoral levels of DNA-platinum adduct. We need at least 20 patients in each arm to delineate the effect of treatment regimen (weekly vs. 3 weekly) on intratumoral adduct levels and the outcome.

Plasma cisplatin levels

Plasma concentrations of total cisplatin will be determined using inductively coupled plasma mass-spectrometry (ICP-MS) using the method described by Shikanov et al.[21] A single 20 mL blood sample will be collected in heparinized tubes on days 1 ± 2 days, 15 ± 2 days, and 36 ± 2 days each, just before RT. Sample will be centrifuged at 5000 × g for 20 min at 4°C to obtain plasma. Plasma will be separated and stored at −20°C till further analysis.

WBC platinum-DNA adducts

DNA platination in the WBC will be determined by a four-step procedure consisting of isolation of WBC out of whole blood, separation of DNA, quantification of DNA, and quantification of platinum bound to DNA. In brief, WBC will be isolated within 2 h after blood collection using density gradient centrifugation. Two bands (mononuclear and polymorphonuclear cells) will be harvested and pooled. Then, the cells will be washed twice with ice-cold PBS to remove other blood components and the gradient medium. WBC samples will be immediately frozen and stored at −20°C until further analysis. The isolation of DNA out of WBC will be performed by solid-phase extraction with QIAamp DNA-blood kits (Qiagen, Hilden, Germany). The isolation procedure consists of the lysis of WBC and adsorption of DNA to a silica membrane followed by two washing steps to remove other cell components. In the last step, DNA would be eluted from the column. All DNA samples will be stored at −20°C until further analysis. The quantification of platinum bound to DNA will be performed by competitive ELISA technique.[22]

Intratumoral levels

Patients undergoing definitive chemoradiation will be subjected to a biopsy of the tumor on 19 ± 2 days for the determination of intratumoral levels of cisplatin. Briefly, a portion of the biopsy specimen will be frozen at −20°C, embedded, and sectioned into 50–100 μm thick sections in a cryostat at −20°C. The sections will be weighed, decomposed in nitric acid, and diluted in DDW before analysis using ICP-MS.[21]

The decision as to whether the day 19 biopsy will be done will be made only after discussion in the head-and-neck multidisciplinary meeting. We are planning the day 19 biopsy in only those patients receiving definitive CRT, which is about 30%–50% of the total sample size. Assuming that 50% would receive definitive CRT, the number of eligible patients would be approximately 130. Since participation in this exploratory study is optional, we are expecting not more that 50% of these eligible subjects to consent. Thus, only 60–70 patients are expected to consent. Moreover, biopsy could be permissible (at joint clinic's discretion) in only 60%–70% of these subjects. Therefore, eventually, we may be able to enroll 40–45 patients on this study.

Cisplatin-DNA adducts in tumor

The same biopsy specimen will also be used for the quantification of cisplatin-DNA adducts. An ELISA method as described by Poirier et al. will be used to measure binding of cisplatin to DNA in tumor tissue.[23]

DNA damage and apoptosis

The extent of apoptosis and DNA damage induced by either regimen will be evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay[24] and alkaline single cell gel electrophoresis (comet) assay.[25]

Analysis of cell cycle

A flow cytometry technique[26] will be used for the analysis of cell cycle in tumor samples obtained from patients undergoing definitive chemoradiation. The nature of distribution of cells in different stages of cell cycle will be compared between the two regimens.


  Adverse Events Top


Information about all adverse events will be collected and recorded and followed up as appropriate. An adverse event is any undesirable sign, symptom, or medical condition occurring after starting study treatment, even if the event is not considered to be treatment-related.

Medical conditions/diseases present before starting the study treatment are only considered adverse events if they worsen after starting study treatment. Clinical events occurring before starting the study treatment but after signing the informed consent form are recorded on the medical history/current medical conditions case report form only if the patient receives study treatment. Abnormal laboratory values or test results constitute adverse events only if they induce clinical signs or symptoms or require therapy, when they are recorded on the adverse events case report form under the signs, symptoms, or diagnosis associated with them.

As far as possible, each adverse event will also be described by:

  • Its duration (start and end dates)
  • The severity grade (mild, moderate, severe)
  • Its relationship to the study drug (suspected/not suspected)
  • The action(s) taken.


Serious adverse events

Information about all serious adverse events (SAEs) will be collected and recorded on the SAE report form within 24 h of learning of its occurrence. An SAE is defined in general as an untoward (unfavorable) event which:

  • Is fatal or life-threatening
  • Required or prolonged hospitalization
  • Was significantly or permanently disabling or incapacitating
  • Constitutes a congenital anomaly or a birth defect
  • May jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above.


Events not considered to be SAEs are hospitalizations occurring under the following circumstances: were planned before entry into the clinical study; are for elective treatment of a condition unrelated to the studied indication or its treatment; occur on an emergency, outpatient basis and do not result in admission (unless fulfilling the criteria above); are part of the normal treatment or monitoring of the studied indication and not associated with any deterioration in condition.

Any SAE occurring after the patient has provided informed consent, and until 4 weeks after the patient has stopped, the study participation must be reported. This includes the period in which the study protocol interferes with the standard medical treatment given to a patient (e.g., treatment withdrawal during washout period, change in treatment to a fixed dose of concomitant medication). SAEs occurring more than 4 weeks after the study discontinuation need only be reported if a relationship to the study drug (or therapy) is suspected.

Special safety-related procedures/instructions for rapid notification of serious adverse events

To ensure patient safety, all SAEs must be reported by the investigator to the ethics committee within 7 days of learning of its occurrence, even if it is not felt to be treatment-related. Follow-up information about a previously reported SAE must also be reported within 24 h of the investigator receiving it. SAE reports should be forwarded to:

Dr. Vanita Noronha, Department of Medical Oncology, Tata Memorial Hospital, Room No. 18, Dr. E. Borges Road, Parel, Mumbai - 400 012, Maharashtra, India. Phone: 24177214.

Statistical analysis

Sample size

The test statistic used is the one-sided Z-test (unpooled). The significance level of the test is targeted at 0.0500. Sample sizes of 132 in arm A and 132 in arm B achieve 80% power to detect noninferiority for the case when the actual treatment group proportion is 0.600. This was calculated based on the primary end point of locoregional control. Assuming an attrition rate of 5% patients per year, the total number of patients needed to be accrued will be approximately 300 patients.

The relation between the chemoradiation regimen, cisplatin pharmacokinetics, and the pharmacodynamic outcome (DNA damage and apoptosis) will be analyzed using analysis of covariance.


  Feasibility of the Study Top


We see approximately 5000 patients with locally advanced head-and-neck carcinoma each year at Tata Memorial Hospital. Assuming that about 10% of patients can be screened per year and that about 40% of patients screened can be randomized, we should be able to accrue 150 patients per year. It will therefore take us 2 years to complete the targeted accrual of 300 patients.


  Ethical Considerations Top


Both weekly and 3-weekly cisplatin-based chemotherapy with RT are the standard of care in different centers; hence, in both the arms, patient will be receiving standard treatment.

Relevant information in lay terms will be provided for patients [Appendix 1], and written informed consent will be obtained [Appendix 2].

The study will be conducted in compliance with the ICMR Statement on Human Experimentation, the Declaration of Helsinki, and the International Committee of Harmonisation Harmonised Tripartite Guidelines for Good Clinical Practice.

The investigator or a person designated by him/her will collect informed consent from all participants, before which the investigator or co-investigator must inform each participant the objectives, benefits, risks, and requirements of the study. He/she will also provide the participant with an information sheet in clear, simple language. The study participant will be allowed ample time to inquire about details of the study and to decide whether or not to participate in the study. The study will not commence until approval has been obtained from the Tata Memorial Hospital Human Ethics Committee.


  References Top


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  2. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-44.
  3. Adelstein DJ, Li Y, Adams GL, Wagner H Jr., Kish JA, Ensley JF, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92-8.
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  8. Gupta T, Agarwal JP, Ghosh-Laskar S, Parikh PM, D'Cruz AK, Dinshaw KA. Radical radiotherapy with concurrent weekly cisplatin in loco-regionally advanced squamous cell carcinoma of the head and neck: A single-institution experience. Head Neck Oncol 2009;1:17.
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  13. Jain RK, Kirar P, Gupta G, Dubey S, Gupta SK, Goyal J. A comparative study of low dose weekly paclitaxel versus cisplatin with concurrent radiation in the treatment of locally advanced head and neck cancers. Indian J Cancer 2009;46:50-3.
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Abstract
Introduction
Materials and Me...
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Discussion
Conclusion
Supplementary Ap...
Introduction
Investigation Plan
Simulation
Definition of Vo...
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Clinical Target ...
Clinical Target ...
Clinical Target ...
Bilateral Neck I...
Delineation of N...
Positive Neck Nodes
Negative Neck Nodes
Planning Target ...
Treatment Planning
Imrt Planning
Dosimetry, Dose ...
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Dose Homogeneity
Dose Constraints
Spinal Cord
Field Verification
Adjuvant Radioth...
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Quality of Life ...
Nutritional Asse...
Pk/pd Correlation
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