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Late Toxicities Among Laryngopharyngeal Cancers Patients

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Background

Laryngo-pharyngeal cancers comprise 1-2% of all cancers worldwide. Pharyngeal cancers (excluding nasopharynx) account for 6.6% and laryngeal cancers 4.8% of all cancers in men and 0.5% and 1 % in women respectively.1 In India, head and neck cancers are one of the most common cancers among males. Of laryngo-pharyngeal cancers hypopharyngeal cancer is more common in males and females. In India, as per the cancer registry reports, the incidence of hypopharynx and laryngeal cancers are ASR- 2.1-6. among males and 0.3-1.8 among females and 3.5-9.7 among men and 0-1.3 among women respectively.

Concurrent Chemo radiation (CT-RT) is currently the standard of care in laryngo-pharyngeal squamous cell carcinomas. CT-RT has been shown to be better than sequential radiotherapy (following induction chemotherapy) and radiotherapy alone in terms of preservation of larynx.

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CT-RT schedule using high-dose cisplatin 100mg/m2 thrice weekly, in combination with standard radiotherapy is the most widely used schedule. The addition of concurrent chemotherapy to radical external beam radiotherapy is often associated with increased toxicity and affects patient compliance with treatment completion. Unlike acute toxicities which can be usually managed with symptomatic measures, late toxicities are often underestimated and ill managed. Mostly supportive care is the only management against such significant morbidity. During CT-RT for laryngeal and pharyngeal cancers, structures involved in deglutition are exposed to higher doses of radiation due to proximity to gross tumour volumes. This can cause dysphagia, stenosis/strictures or recurrent episodes of aspiration and patient becomes dependent on Ryle’s tube or feeding gastrostomy/jejunostomy tube. Also it may cause laryngeal oedema and strider or cartilage necrosis and this necessitates tracheotomy or laryngectomy respectively.7 Due to poor tolerance observed with the 3 weekly regime some institutions practice the weekly regime of concurrent cisplatin at a dose of 30 mg/m2 or 40 mg/m2.

Various radiotherapy schedules (Conventional fractionation, hyperfractionation Simultaneous Integrated Boost, Concomitant boost technique etc) are also being used in treatment of laryngopharyngeal cancers. However studies showing inter-comparison between different chemo-radiation schedules and the associated toxicities are few.

In this retrospective study we have assessed the acute and late toxicities of radiotherapy on laryngopharyngeal cancer patients and tried to analyze the factors associated with late toxicities in particular. The impact of different concurrent chemotherapy schedules on the patterns of late toxicity has been emphasized in this research.

Methodology

This is a retrospective cohort study involving review of patient records. All the patients with laryngo-pharyngeal cancers treated with concurrent chemo-radiation using Volumetric Modulated Arc Therapy Technique (VMAT) during January 2012 to December 2015. The study was conducted during June 2016- Nov 2016.

The patients with nasopharyngeal carcinoma and patients treated with techniques other than VMAT, patients who were on feeding tubes and those who had to undergo tracheostomy prior to start of RT were excluded from the study.

At our centre locally advanced laryngopharyngeal cancers [Stage T3, T4 (excluding cartilage invasion) and node positive] are treated with concurrent chemoradiation. Radiotherapy is delivered by using Volumetric Modulated Arc Therapy (VMAT) using conventional fractionation or Simultaneous Integrated Boost technique. Patients with Eastern Cooperative Oncology Group (ECOG) performance status I are selected for concurrent chemo-radiation and Cisplatin is administered 40 mg/m2 weekly or 100 mg/m2 thrice weekly.

After diagnosis and staging work, treatment plan (CT-RT) was concurred in the multispecialty board. All patients were seen by dietician and speech and swallowing therapist before radiotherapy planning. Cardiology, pulmonology, dental and ENT (with audiogram) consultations were done before starting treatment. CT scans for RT planning are done on CT simulator (GE………).after immobilising the patient with a thermoplastic mould on an All in One board and contrast enhancing CT scan is done with a slice thickness of 2.5mm. The images are then transferred to the treatment planning system (Eclipse Palo…..). Organs at risk and Target volumes are contoured by as per the Radiation Therapy Oncology Group RTOG contouring guidelines. Patients are treated up to a total dose of 70 Gy in 35 fractions or 69 Gy in 33 fractions, with conventional fractionation or Simultaneous Integrated Boost (SIB) techniques respectively. Radiation planning is done with Volumetric Modulated Arc Therapy Technique (VMAT). Once plans are approved by the oncologists the quality assurance (QA) tests are carried out on octaves phantom. After QA check, treatment plan is transferred to the Linear accelerator ((Varian Clinac iX) and treatment is executed.

Chemotherapy was given from the day of start of radiation therapy, 40mg/m2 weekly schedule or 100mg/m2 3 weekly schedules till the completion of radiotherapy. During radiotherapy, patients were reviewed by oncologists weekly with complete blood counts and biochemistry. Weight and acute toxicities were documented in the radiation records. They were also reviewed by speech and swallowing therapist and dietician at least once in a week. After completion of chemo radiation, patients were followed up at regular intervals by oncologists, speech and swallowing therapist and dietician. Videoflouroscopy and FEES test are done to assess the swallowing function. First follow up after 2 weeks of completion of treatment and second review at 6 weeks after completion of radiation therapy was done. At six weeks direct laryngoscopy and pharyngoscopy (DLDP) was done followed by once in six months or early if symptomatic. Patients were followed up two monthly till six months, three monthly till three years, six monthly from 3-5 years and yearly thereafter. The toxicities are recorded in the case records as per Common Terminology Criteria for Adverse Events CTCAE version 4.

Data were extracted from patient case records and radiation charts into data abstraction form. Demographic (age, sex) and clinical (co-morbidities, TNM staging, treatment schedules, weight loss, doses delivered to larynx, constrictors, toxicities-both acute and severe late toxicities) variables were collected. Data was extracted from routinely filled patient case records without the name or any other personal identifiers.

Data Entry and Analysis

Double data entry and validation were done in EpiData entry version 3.1. Any discrepancy in data entry was resolved by referring to the original data abstraction form. The final validated dataset was imported into EpiData analysis v2.2.2.182 (EpiData Association, Odense, Denmark) for analysis. Descriptive statistics such as proportions were used to summarize incidence of toxicities. Inferential statistics such as chi square and t-test were used to investigate factors associated with severe late toxicities.

Ethics Considerations

The study was approved by the Institutional review board-Ethics committee (IRB no 1616/IRB-SRC/13/MCC/11-06-16/6.) at Malabar Cancer Centre. Approval was obtained from the Union Ethics Advisory Group, Paris, France also

Results

A total of 93 patients with laryngopharyngeal cancers treated with concurrent chemo-radiation were recruited into the study. Among them, 71(87%) were aged 55 and above, majority were males (89, 96%). Oropharynx was found to be the common site of cancer (54, 58%) followed by hypopharynx (20, 22%) and larynx (19. 20%). Among the recruited patients majority had T3 tumours (48, 52%) and N2 disease (36, 39%). About one third (34, 37%) patients received a chemotherapy schedule of 40 mg/m2 weekly whereas (29, 31%) received 100 mg/m2 thrice weekly. Another 30 (32%) received doses other than cisplatin (carboplatin). More than two-third of the patients received 69.3Gy/33 fractions with simultaneous integrated boost schedule whereas the rest underwent 70Gy/35# with sequential schedule.

Table 2 shows the incidence of acute and severe late toxicities by different schedules of CT-RT. Overall, tube dependence was seen in 16 (20%) patients. Around half of the patients had grade III dysphagia and odynophagia on treatment, whereas post-treatment dysphagia and odynophagia was seen in 18 (21%) and 23 (27%) patients respectively. Post treatment aspiration pneumonia was witnessed in nine (10%) patients. Though more than 20% of patients had grade III late dysphagia and tube dependency, dose to constrictors (Mean dose, D60, D50, V60 and V30) did not appear to be significant.

Grade III Laryngeal edema was seen in 18 (21%) patients of whom post-treatment tracheostomy was done in 10 (11%) patients. On dosimetric analysis, dose to 60% volume of larynx (D60), Volume of larynx receiving 50Gy (V50) and 60 Gy (V60) were found to be significantly associated with severe late toxicity. Necrosis of cartilage and laryngectomy occurred in two (2%) Stricture at the level of cricopharynx to oesophagus was found in six (7%) patients. More than 10% weight loss was seen in one third (34.4%) of patients. Other factors which were found to be significantly associated with severe late toxicity were site of cancer, node positivity and weight loss. though more than 20% of patients had grade III dysphagia.

Only one patient completed all seven cycles of chemotherapy at a dose of 40 mg/m2. Nearly 26% of patients on cisplatin (40 mg/m2 dose) completed 06 cycles, whereas 60% completed at least five such cycles of chemotherapy. Only one patient could complete all three cycles of cisplatin at a dose of 100 mg/m2 and three-fourth could complete at least two such cycles.

Nearly 84% of patients receiving 69.3 Gy/33# completed the schedule without any break. Only two (03%) patients had a break longer than 7 days. Similarly among patients receiving 70 Gy/35#, 72% completed without any break and none had a break more than 7 days.

Reasons for RT break and Chemotherapy break were Aspiration Pneumonia (10,11%), poor compliance (7,8%), grade III vomiting in 2 patients, deranged RFT(7,8%), Grade III and above hyponatremia in, grade III skin reaction in febrile neutropenia in poor compliance in <5% patients. Association of compliance with age were also analysed and is depicted in Figure 2.

Treatment break is found to be more with patients with age > 65. One patient with age <45 yrs had break of more than 10 days

Discussion

Concurrent chemo-radiation is a globally accepted organ preservation treatment protocol in laryngo-pharyngeal cancers.3 the concern over early and late toxicities of this protocol has been a subject of long standing debates and discussion. Significant morbidity mostly accompanies this aggressive mode of treatment. Hence the factors contributing to the toxicities need to be identified so that timely precautions can be taken to reduce the anticipated morbidity. The factors such as demographic characteristics, dosimetric data, treatment techniques, schedule of concurrent chemotherapy, etc have been analysed from the data records. Our study aims to provide an insight into those factors which are particularly responsible for late toxicities.

This study to assess the treatment related toxicities in laryngeal and pharyngeal cancers treated with concurrent chemo-radiation using Volumetric Modulated Arc Therapy (VMAT) is one of the few reported in Indian population. In low middle income group countries, the support system for patients outside cancer hospitals is rather insufficient and less efficacious. In this study, overall 31% of patients had severe late toxicity. Compared to other sites oropharyngeal primaries had statistically significant association with late toxicities. Though during treatment of laryngeal and hypopharyngeal cancers larger volumes of larynx received higher doses of radiation, they did not appear to be significantly associated with toxicity. The probable reason may be that oropharyngeal cancers had higher T and N stage compared to the other two sites. In laryngeal and hypopharyngeal cancers patients with T4 disease were treated with surgery as per the Institutional protocol. Dose to larynx D60, V50 and V60 showed a statistically significant association with severe late toxicities. This may be due to large volume tumors at presentation leading to larger target volume. Hence dose constraints to larynx might not be achieved.

In our study the incidence of severe dysphagia was 21% and the tube dependence for more than 6 months was 20%. Though more than 20% of patients had grade III late dysphagia and tube dependency, dose to constrictors (Mean dose, D60, D50, V60 and V30) did not appear to be significantly related. Various studies on morbidity analysis of concurrent chemo radiation in advanced head and neck cancers have shown that the incidence of tube dependence for a duration of 6 months and 12 months as 36% and 17-30%.

But dosimetric correlation with tube dependency has not been described so far.

Post treatment aspiration pneumonia was witnessed in nine (10%) patients. More than 10% weight loss was seen in one third (34.4%) of patients. Many studies have reported median weight loss during treatment as percentage of initial weight and it was reported to be 10-12 %. The possible relation of weight loss and aspiration pneumonia has been hypothesized by N. P. Nguyen 5 In our series other factors found to be significantly associated with severe late toxicity were site of cancer, node positivity and weight loss.

In this series, for the low dose weekly schedule, 60% of patients completed at least 5 cycles, but only one patient could complete all seven cycles. Similarly for the standard three weekly schedule, only one patient could complete all three cycles of chemotherapy and three-fourth could complete at least two such cycles. This is in sharp contrast to the data available from RTOG 0129 trial. Failure to complete the planned number of chemotherapy cycles were due to the presence of poorer prognostic factors that precluded tolerance to the toxic treatment. In our series, most patients had high volume disease that warranted irradiation of larger volume of tissues. In addition, poor nutritional status when compared to western population may also be a factor. Preoperative optimization of nutritional status and perioperative aggressive nutritional therapy may be required to improve the chemotherapy completion rates and reduction in morbidity rates.

84% and 72% of patients receiving 69.3 Gy/33# and 70 Gy/35# completed the schedule without any break. Only two (03%) patients had a break longer than 7 days. The causes of treatment interruptions were aspiration Pneumonia, poor compliance, grade III acute toxicities of vomiting and hyponatremia. Tejpal etal has reported a study using low weekly dose of cisplatin in concurrent chemoradiation in advanced head and neck cancers in Indian scenario. In this study, an interruption rate of 15% was reported. Hospitalization for supportive care was required in 7.5% of patients. Only 2% of patients dropped out of the treatment and these were unrelated to treatment.

Being a retrospective analysis, the inherent biases and shortfalls are well kept in consideration. Firstly it is likely that many factors which significantly predicted the morbidity could have been missed out. Secondly missing entries on various morbidities with their grades could have led to ineligibility for inclusion in analysis.

Conclusion

Concurrent chemoradiation for organ preservation protocols of laryngral and pharyngeal cancers is a toxic treatment with significant morbidity. Volumetric arc therapy as radiotherapy protocol can be incorporated with an attempt o reduces the morbidity. The major factors related to the late toxicities include the site of cancer, node positivity and weight loss associated with treatment and disease. Dose to larynx has an important association in the dysphagia and tube dependence, but dose to constrictors do not appear to have any significant association. With the drawbacks of retrospective analysis , the study may provide guidance to future prospective studies on dosimetric analysis with respect to morbidity and development of planning methods to counter preventable morbidity.

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