Prospective Observational Comparative Study of Response and Toxicities in Early Glottic Cancer Using Telecobalt Versus 3D-CRT

Abstract

The study was performed with 50 patients, 24 patients in Arm A and 26 patients in Arm B. Arm A—Conventional Telecobalt RT 66 Gy/33 fraction in stage T1N0M0 and stage T2N0M0 and Arm B—3D-CRT 66 Gy/33 fraction in T1N0M0 and T2N0M0 used. At the end of RT, 6 weeks, 3 months acute and late toxicities were noted by RTOG/EORTC morbidity scoring criteria for skin reaction, dysphagia and laryngeal toxicity. Fiber optic Laryngoscopy clinical assessment criteria were used to assess response after 6 weeks, 3 months of treatment completion. At 6 weeks of follow-up—Both Arm A and B complete response rate were 83.3% and 88.5% respectively and at 3 months rate were 85.0% and 95.7% respectively. There was no superiority of results with 3D-CRT over 2DRT. At the end of RT dysphagia grade 3 toxicity seen 1 patient (4.2%) but in Arm B (total 26 patients) no grade 3 toxicity found. At the end of 6 week and 3 month, one patient (4.3%) had grade 3 toxicity on Arm B only at 3 month. All these results are comparable. At the end of RT, one patient (3.8%) had incidentally dermatitis grade 3 toxicity in Arm B only. But all the results are comparable. On follow up, 6 week and 3 months, no grade 3 toxicity noted. At the end of RT, grade 3 laryngeal toxicity noted in 3 (12.5%) in Arm A and 2 (7.7%) in Arm B, not statistically significant. At 6 week, grade 3 toxicity found in 3/24 (12.5%) in Arm A and 2/26 (7.7%) in Arm B, at 3 months, 1/26 (4.3%) patient had incidental grade 3 toxicity only in Arm B. As conformal radiotherapy is more time consuming, less available in India and more costly than 2DRT, we can consider Conventional 2D planning for patients in India where most of people belong to low economic profile. Due to limitation in sample size and long-term follow-up further randomized studies are needed to validate the results.

Introduction

Cancer of the larynx presents 2% of the total cancer risk and is the most common head and neck cancer excluding skin [1]. According to Globocon 2018, the incidence and mortality of cancer of larynx 2.76% and 2.47% respectively in India [2]. Radiotherapy (RT) considered curative in early glottic cancer, voice preserving; avoiding the total laryngectomy [3, 4]. It is the initial treatment in most centre and surgery is kept for salvage therapy for RT failure [5, 6]. Also, radiotherapy gives higher rate of local control than vocal cord stripping or laser excision [7]. We can use either conventional simulator based Telecobalt therapy or CT scan/3D TPS based planning where the cost is much higher and mostly concentrated in a handful of metropolitan cities. Conversely, conventional Telecobalt RT machine is more easily available, economic and excellent results documented specially in T₁ and T₂ vocal cord cancer [8–10].

Both simulator based conventional planning (for Telecobalt) and CT scan/TPS (treatment planning system) based planning (for Linear accelerator) are routinely employed in radiotherapy planning of T₁ and T₂ glottic carcinoma. The results are good in both types of planning although they have never been compared systematically.

Aims and Objectives

1. To compare the clinical response between two treatment modalities at 6 weeks and at 3 months after completion of treatment.

2. To compare the toxicities (in regard to skin toxicity, dysphagia, laryngeal toxicity) between two treatment modalities at the end of radiation, at 6 weeks and at 3 months after completion of treatment.

Materials and Methods

Methodology

1. Source of data:

   This prospective observational study was conducted between from June 2017 to July 2018.

2. Pretreatment evaluation:

   Complete clinical history; systemic examination and local examination of regional lymph nodes were done. Patients were investigated with routine investigations like, blood investigations (complete heamogram/RFT/LFT), chest x-ray (PA), dental evaluation, and Contrast enhanced CT scan of head and neck region. Patients were also evaluated at ENT department by routine Fiber Optic Laryngoscopy (FOL) exam and biopsy from the lesion. All patients were staged according to AJCC TNM staging Manual 8th edition.

3. Consent of the patient:

   Patient’s informed written consent was obtained in their own vernacular language. Patient information leaflet was provided to every patient.

4. Inclusion criteria:

   1. Age
   2. Sites glottic carcinoma of stage _cT_1-2 N₀ M₀.
   3. Performance status ECOG < 2.
   4. Hematological and biochemical parameters:
      Hb > 10 g/dl
      Absolute neutrophil count > 1500/mm³
      Platelet count > 100,000/mm³
      BUN < 25 mg/dl
      Serum creatinine < 1.5 mg/dl
      Serum bilirubin < 1.5 mg/dl
      ALT and AST within normal limits.
   5. No history of prior radiation to head and neck region.
   6. No history of major medical illness.
5. Exclusion criteria:

   1. Patients previously treated with Radiotherapy or chemotherapy due to any cause.
   2. Stages III or IV tumors.
   3. Recurrent tumors.
   4. Diseases with distant metastasis.
   5. Performance status > 2.
   6. Pregnant or Breast feeding women.
   7. Medically unfit patients including patients suffering from severe cardiopulmonary disease, uncontrolled diabetes, residual paralysis from CVA and immunocompromised patients.
   8. History of any prior radiation to head and neck region.

6. Parameters to study:

   Response After radiotherapy, the response was evaluated by clinical, direct laryngoscopy ENT examinations (FOL) at the end of RT, 6 week and 3 months.

   Toxicities Toxicity studies were done weekly during treatment at the end of RT and at 6 week, 3 months of completion of treatment. Toxicities studies will include:

   1. Dermatitis
   2. Dysphagia
   3. Laryngeal toxicities

   Grading was done according to RTOG grading system [11, 12].

7. Study design:

   A prospective observational nonrandomized comparative study.

8. Grouping of patients:

   The “Arm A” consisted of patients planned for Conventional Telecobalt RT and “Arm B” consisted of patients planned for 3DCRT.

9. Treatment Plan of Arm A: Radiotherapy Protocol

   Field Borders

   • Superior—mid-body of the hyoid.
   • Inferior—inferior margin of cricoids cartilage.
   • Anterior—beams are allowed to flash 1 cm.
   • Posterior—anterior vertebral column.

   Technique patients were treated with two parallel opposed lateral fields. Simulation x-ray film was taken for verification of radiation portals and necessary corrections were made before start of treatment (Fig. 1). Telecobalt Theratron Elit-80 has gamma ray energy of 1.25 MeV. The trimmer bars (SSD-cm).Maximum field size 35 × 35 cm² and Minimum field size 5 × 5 cm².

   Dose Prescription Patients received 66 Gy in 33 fractions for T1, T2 lesions over 6.5 weeks in 2-Gy fractions, 5 fractions/week [13].

   Arm B: Radiotherapy Protocol

   Energy Patients were treated with 6 MV Linear accelerator machine with MLC (3DCRT planning).

   Target Volume Target volume contain primary tumor only.

   Dose Prescription Patients received 66 Gray (Gy) in 33 fractions for T1, T2 lesions over 6.5 weeks given in 2-Gy fractions. Five fractions/week [13].

   RT Techniques For conformal radiation, CT (Computed tomography) scan simulation done (Fig. 2) before start of the treatment and contouring of target lesion. CT slices of 3 mm thick are obtained from the base of skull to the top of the aortic arch with the patient immobilized in the treatment position.

   Radiotherapy volumes for glottic cancer patients are based on the International Commission on Radiation Units and Measurements (ICRU) 50 and 62. The GTV includes primary tumor involving glottis and extension to transglottis or subglottis (extension based on endoscopic and imaging findings). Clinical target volume (CTV). Extension of 2 cm from the GTV to form the CTV. CTVs are expanded to account for organ motion and setup uncertainity ideally based on institution-specific data to form the PTV (Fig. 3).

   During plan evaluation target is 95% of the isodose (treated volume) should cover 100% of the PTV. Siemens Primus Linear Accelerator has single photon energy of 6 MV and six electron energies such as 5, 7, 8, 10, 12 and 14 MeV used for treatment and ONCENTRA 4.3 computer software was used for planning purposes.

10. Treatment Monitoring:

    Acute toxicities were assessed once weekly. Response was assessed clinically by Fiber Optic Laryngoscopy (FOL) assessment criteria. Toxicities assessed according to EORTC/RTOG toxicity guideline

11. Follow-up

    The first follow-up was done after completion of treatment. During follow-up the patients were assessed, FOL done at 6 week and at 3 months during follow up assessment of overall response rates and toxicities.

Fig. 1.

X-ray simulation film for radiation field for glottis cancer

Fig. 2.

CT simulation of the patient of Glottic cancer. Infrared Laser beams used for marking with the help of lead marker (oblique view of photgraph)

Fig. 3.

3D-TPS based planning for 3D-CRTs

Results and Analysis

Data Analysis

For statistical analysis data were entered into a Microsoft excel spreadsheet and then analyzed by SPSS 20.0.1 and GraphPad Prism version 5. Data have been summarized as mean and standard deviation for numerical variables and count and percentages for categorical variables. The median and the interquartile range have been stated for numerical variables that are not normally distributed. Student’s independent sample’s t test was applied to compare normally distributed numerical variables between groups; unpaired proportions were compared by Chi square test or Fischer’s exact test, as appropriate. Z-test (Standard Normal Deviate) was used to test the significant difference between two proportions.

Explicit expressions that can be used to carry out various t tests are given below. In each case, the formula for a test statistic that either exactly follows or closely approximates a t-distribution under the null hypothesis is given. Also, the appropriate degrees of freedom are given in each case. Each of these statistics can be used to carry out either a one-tailed test or a two-tailed test.

Once a t value is determined, a p value can be found using a table of values from Student’s t distribution. If the calculated p value is below the threshold chosen for statistical significance (usually the 0.10, the 0.05, or 0.01 level), then the null hypothesis is rejected in favour of the alternative hypothesis.

p value ≤ 0.05 was considered for statistically significant.

In this study initially it was proposed to include 60 patients, 30 in Arm A and 30 in Arm B. Out of those, 2 patients in each group (total of 4 patients) defaulted the treatment protocol and 4 patients in Arm A and 2 patients in Arm B (total of 6 patients) were lost to follow-up. So, 50 patients, 24 patients in Arm A and 26 patients in Arm B were taken for final analysis.

Evaluation of Overall Response (Table 1, Fig. 4)

Table 1.

Overall response to treatment in two arms

Response evaluation	Response	Arm-A		Arm-B		p value
		No.	%	No.	%
6 weeks response	CR	20	83.3	23	88.5	0.5157
	PR	4	16.7	3	11.5	0.59612
3 months response	CR	17	85.0	22	95.7	0.2584
	Recurrence	3	15.0	1	4.3	0.1585

Fig. 4.

Overall response

At 6 weeks of follow-up Both Arm A and B complete response (CR) rate were 83.3% and 88.5% respectively. This difference was not statistically significant (p > 0.05). Arm A had partial response (PR) rate of 16.7% and Arm B had partial response rate of 11.5%. This difference was not statistically significant (p > 0.05)

At 3 months of follow-up Both Arm A and B complete response rate were 85.0% and 95.7% respectively. This difference was not statistically significant (p > 0.05). Arm A had recurrence rate of 15.0% and Arm B had recurrence rate of 4.3%. This difference was not statistically significant (p > 0.05).

Evaluation of Overall Dysphagia Toxicity (Table 2, Fig. 5)

Table 2.

Overall dysphagia

Overall dysphagia toxicity	Arm-A		Arm-B		p value
	No	%	No	%
End of RT dysphagia
Grade 1	15	62.5	16	61.5	0.9442
Grade 2	8	33.3	10	38.5	0.7039
Grade 3	1	4.2	0	0.0	0.2937
Dysphagia 6 weeks
Grade 0	10	41.7	6	23.1	0.1585
Grade 1	7	29.2	6	23.1	0.6241
Grade 2	7	29.2	14	53.8	0.0767
Dysphagia 3 months
Grade 0	15	75.0	15	65.2	0.7263
Grade 1	2	10.0	7	30.4	0.0872
Grade 2	3	15.0	0	0.0	0.0628
Grade 3	0	0.0	1	4.3	0.3472

Fig. 5.

Overall dysphagia

End of RT dysphagia Grade 1:15 (62.5%), Grade 2:8 (33.3%), Grade 3:1 (4.2%) in Arm A and was Grade 1:16 (61.5%), Grade 2:10 (38.5%) in Arm B. Comparison between two arms p values were in Grade 1 (p = 0.9442), Grade 2 (p = 0.7039) and Grade 3 (p = 0.2937).

At 6 weeks Grade 0:10 (41.7%), Grade 1:7 (29.2%), Grade 2: 7 (29.2%) in Arm A and was Grade 0:6 (23.1%), Grade 1:6 (23.1%), Grade 14: 7 (53.8%) in Arm B. Comparison between two arms p values were in Grade 0 (p = 0.1585), Grade 1 (p = 0.6241) and Grade 3 (p = 0.0767).

At 3 months Grade 0:15 (75.0%), Grade 1:2 (10.0%), Grade 2: 3 (15.0) in Arm A and Grade 0:15 (65.2%), Grade 1:7 (30.4%), Grade 3: 1 (4.3) in Arm B. Comparison between two arms p values were in Grade 0 (p = 0.7263), Grade 1 (p = 0.0872), Grade 2 (p = 0.0628) and Grade 3 (p = 0.3472).

Also there was no statistically significant difference between the groups in respect of late toxicity of pharynx and esophagus in all follow-up (p > 0.05).

Evaluation of Overall Dermatitis (Table 3; Fig. 6)

Table 3.

Overall dermatitis

Overall dermatitis	Arm-A		Arm-B		p value
	No	%	No	%
End of RT
Grade 1	16	66.7	17	65.4	0.9203
Grade 2	8	33.3	8	30.8	0.8493
Grade 3	0	0.0	1	3.8	0.3320
At 6 weeks
Grade 0	13	54.2	14	53.8	0.9840
Grade 1	8	33.3	9	34.6	0.9203
Grade 2	3	12.5	3	11.5	0.9203
At 3 months
Grade 0	14	70.0	20	87.0	0.1738
Grade 1	6	30.0	3	13.0	0.1738

Fig. 6.

Overall dermatitis

End of RT Grade 1:16 (66.7%), Grade 2:8 (33.3%) in Arm A and was Grade 1:17 (65.4%), Grade 2:8 (30.8%), Grade 3:1 (3.8%) in Arm B. Comparison between two groups p values were in Grade 1 (p = 0.9203), Grade 2 (p = 0.8493) and Grade 3 (p = 0.3320).

At 6 weeks Grade 0:13 (54.2%), Grade 1:8 (33.3%), Grade 2: 3 (12.5%) in Arm A and was Grade 0:14 (53.8%), Grade 1:9 (34.6%), Grade 2: 3 (11.5%) in Arm B.

Comparison between two groups p values were in Grade 0 (p = 0.9840), Grade 1 (p = 0.9203) and Grade 2 (p = 0.9203).

At 3 months Grade 0:14 (70.0%), Grade 1:6 (30.0%) in Arm A and Grade 0:20 (87.0%) and Grade 1:3 (13.0%) in Arm B. Comparison between two groups p values were in Grade 0 (p = 0.1738) and Grade 1 (p = 0.1738).

Also there was no statistically significant difference between the arms in respect of dermatitis in all follow-up (p > 0.05).

Evaluation of Overall Laryngeal Toxicity (Table 4; Fig. 7)

Table 4.

Overall laryngitis

Overall laryngitis	Arm-A		Arm-B		p value
	No	%	No	%
End of RT
Grade l	16	66.7	20	76.9	0.4179
Grade 2	5	20.8	4	15.4	0.6170
Grade 3	3	12.5	2	7.7	0.5686
6 weeks
Grade 0	7	29.2	3	11.5	0.1187
Grade l	5	20.8	10	38.5	0.1738
Grade 2	9	37.5	11	42.3	0.7263
Grade 3	3	12.5	2	7.7	0.5686
3 months
Grade 0	15	75.0	17	73.9	0.9362
Grade l	4	20.0	4	17.4	0.8258
Grade 2	1	5.0	1	4.3	0.9203
Grade 3	0	0.0	1	4.3	0.3472

Fig. 7.

Overall laryngitis

End of RT Grade 1:16 (66.7%), Grade 2:5 (20.8%), Grade 3:3 (12.5%) in Arm A and was Grade 1:20 (76.9%), Grade 2:4 (15.4%), Grade 3:2 (7.7%) in Arm B. Comparison between two arms p values were in Grade 1 (p = 0.4179), Grade 2 (p = 0.6170) and Grade 3 (p = 0.5686).

At 6 weeks Grade 0:7 (29.2%), Grade 1:5 (20.8%), Grade 2:9 (37.5%), Grade 3:3 (12.5%) in Group A and was Grade 0:3 (11.5%), Grade 1:10 (38.5%), Grade 2:11 (42.3%), Grade 3:2 (7.7%) in Group B. Comparison between two groups p values were in Grade 0 (p = 0.1187), Grade 1 (p = 0.1738), Grade 2 (p = 0.7263) and Grade 3 (p = 0.5686).

At 3 months Grade 0:15 (75.0%), Grade 1:4 (20.0%), Grade 2:1 (5.0%) in Arm A and was Grade 0:17 (73.9%), Grade 1:4 (17.4%), Grade 2:1 (4.3%), Grade 3:2 (4.3%) in Arm B. Comparison between two Arms p values were in Grade 0 (p = 0.9362), Grade 1 (p = 0.8258), Grade 2 (p = 0.9203) and Grade 3 (p = 0.3472).

Also there was no statistically significant difference between the arms in respect of laryngeal toxicity in all follow-up (p > 0.05).

Discussion

Conventional radiotherapy (2DRT) is the standard technique for vocal cord or glottis cancer in many centers of India while other centers have replaced this technique by 3-Dimensional Conformal RT (3D-CRT) or other forms of conformal radiation like IMRT (Intensity Modulated Radiation Therapy), which is associated with comparable target coverage with normal tissue sparing [14].

Response Evaluation

Radiation is the promising approach for treating the early vocal cord cancer as proved from many literature since historic era [15–19].

The voice is preserved in more than 80% of patients treated with radiotherapy [18] and primary surgical therapy has not shown results superior to those obtained by primary radiotherapy with surgery held in reserve [17, 20]

In our study, we reported the overall treatment response rates between the Conventional 2DRT group and 3D-CRT group at 6 weeks and 3 months of follow-up. At 6 week, arm A had 83.3% CR and 16.7% PR while arm B had 88.5% CR and 11.5% PR respectively. There was no statistical difference between the two groups studied. At 3 months, CR 85% and recurrence 15% in arm A while CR 95.7% and recurrence 4.3% in arm B. Although the number of recurrence and PR is more in arm A than that of arm B, It was also not significant statistically (p > 0.05).

A study by Lim et al. [21] included 438 patients of T1–T2 N0 glottic cancer and used beam energies 60Co and 4-MV or 6-MV photons. 5 year OS rate was 91.7%, local recurrence-free survival (LRFS) and LRFS with voice preservation were 87.8% and 90.3%, respectively in early glottic cancer. The Relapse occurred at 1.4 years over ipsilateral vocal cord only. Definitive RT achieved a high cure rate, voice preservation, and tolerable toxicity in early glottic cancer

In a retrospective study by Lee et al. [22] in 2001, assesses the efficacy of 6 MV compared with CO-60 radiation therapy in 128 patients. Overall 3-year actuarial local control rates for T1 and T2 carcinomas were 86% and 68%, respectively. Lesions involving the posterior third of the vocal cord had significantly worse 3-year local control (76% vs. 86%, p = 0.038). Radiation therapy technique and overall treatment time did not significantly affect local control. Three-year local control was 76%, with doses less than 6600 cGy and 90% with higher doses. The use of 6-MV photons for treatment of early glottic cancer seems to achieve local control similar to that reported with lower-energy photons.

Izuno et al. [23] included T1No Mo glotic cancer patients of total 53, out of which 17 treated in Co 60, 25 in 8 or 10 MV X-rays and 11 with 4 MV X-rays and results compared. No statistically significant difference in the actuarial survival rate was observed between the Co 60 and 8/10 MV groups. The actuarial 5-year survival rate was 94% in the Co 60 group and 92% in the 8/10 MV group. The values are comparable to those previously reported. 5 year local control rate 88% on Co 60 and 60% in 8/10 MV photon.

In a prospective study by Fein et al. [24] included 109 patients of T1–2 N0 M0 glottic cancer treated with cobalt 60 and 6 MV photon and followed up for average 83 months. The 2-year local control rate for patients treated with 60Co was 83% versus 92% for patients treated with 6 MV x-ray. Hence, all these results corroborate with our study results

On the contrary, results of treatment with 6 MV photon in early glottis cancer conflicting, some authors reported comparable results with lower energies while others raised concern about poor outcome [23, 25–28].

Toxicity Profile

During radiation, some acute (at the end of RT) and late (at 6 week, 3 months) toxicities were observed and documented in both groups. In our study, at the end of RT dysphagia grade 3 toxicity seen 1 patient (4.2%) but in Arm B (total 26 patients) no grade 3 toxicity found. At the end of 6 week and 3 month, one patient (4.3%) had grade 3 toxicity on Arm B only at 3 month. All these results are comparable.

Skin toxicity In our study, at the end of RT, one patient (3.8%) had incidentally grade 3 toxicity in Arm B only. But all the results are comparable. On follow up, 6 week and 3 months, no grade 3 toxicity noted.

Laryngeal Toxicity Laryngeal toxicity observed with the help of Fibro optic bronchoscopy (FOL).At the end of RT, grade 3 toxicity noted in 3 (12.5%) in Arm A and 2 (7.7%) in Arm B, not statistically significant.

At 6 week, grade 3 toxicity found in 3/24 (12.5%) in Arm A and 2/26 (7.7%) in Arm B, At 3 months, 1/26 (4.3%) patient had incidental grade 3 toxicity only in Arm B. The female patient with incidental Grade 3 toxicity eventually underwent tracheostomy and admission in ITU for supportive care.

There was no treatment related deaths.

Izuno et al. [23] demonstrated that no major complications of radiation occurred in the comparable groups.

A retrospective study by Foote et al. [25] analyzed 73 patients of early glottic cancer, of these 30 had treatment with cobalt-60 or 4-MV photons and 43 with 6-MV photons. Chondronecrosis did not develop in any of the patients. Grade 3 laryngeal toxicity developed in one patient and required placement of a permanent tracheostomy.

In a prospective study by Hayakawa et al. [28] 117 patients with stage I and stage II glottis cancer treated with Cobalt 60 and 10 MV photons. For Cobalt 60, four patients developed severe laryngeal edema, and two patients had total laryngectomy without local residual tumor. For 10 MV, 16 patients developed local recurrence in 5 years and in 5 of them the tumor exhibited verrucous-like histopathological findings.

Tong et al. [29] reported there was no incidence of grade 3 or higher acute complications in T1 disease. For T2 disease, 1.2% patients experienced grade 3 acute radiation toxicity, 10.4% in patients treated with 2.5 Gy compared with none in those treated with 2.0 Gy (p = 0.001). Eight patients had severe odynophagia and grade III confluent mucositis, requiring nasogastric tube feeding or admission for intravenous fluid supplement. Clinical treatment outcome by 6 MV photons is similar and comparable to historic data of Cobalt-60 and 2 MV photons.

A prospective study by Kim et al. [30] included 157 patients of T1–2 N0 M0 glottic cancer and used 4MV or 6MV radiation. Acute toxicities were grade 2 and managed with symptomatics. There was no significant difference in grade 2 mucositis incidence between the groups: two in the group A (3.1%); and six in the group B (6.5%). No delayed complication of grade 2 or higher was observed during the follow-up.

Conclusion

Thus in the end it can be stated that both RT techniques resulted in similar outcomes and the toxicities were not significantly different. Although in some cased toxicities are more in cobalt and few more number of partial response and recurrence, but results are comparable.

Our study was observational in nature and had limited number of patients and duration of follow-up was also limited. A prospective randomized study with large number of patients and long period of follow-up is needed to conclude about the superiority of Conformal RT versus 2DRT for tumor control as well as radiation morbidity.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.