Research Article

Research Article

Evaluating Therapy Results and Analysis of Immediate and Long-term Treatment Toxicity in a Clinical Case Series of Nasopharyngeal Carcinoma

Carmen Salvador Coloma1, Miguel Pastor Borgoñớn1, Koen Jerusalem2, Óscar Mauricio Niño1, Encarnaciớn Reche Santos1, Joaquίn Montalar Salcedo1.

1Medical Oncology Department, University Hospital La Fe (Valencia-Spain).

2Internal Medicine Department, University Hospital La Fe (Valencia-Spain).

                                     Corresponding author: Dr. Carmen Salvador Coloma. Medical Oncology Department.University Hospital La Fe ( Valencia). Avinguda de   

Fernando Abril Martorel n. 106. 46026 (Valencia). e-mail: salvadorcoloma@gmail.com. Phone number: 0034-605102025.

Citation: Coloma CS, Borgoñớn MP, Jerusalem K, Cui CY, Niño OM, Santos ER, Salcedo JM. Evaluating therapy results and analysis of immediate and long-term treatment toxicity in a clinical case series of nasopharyngeal carcinoma. J Nasopharyng Carcinoma, 2015, 2(5): e26. doi:10.15383/jnpc.26.

Competing interests: The authors have declared that no competing interests exist.

Conflict of interest: None

Copyright: 2015 By the Editorial Department of Journal of Minimally Invasive Orthopedics. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 

         

 

 

 

 

 

 

 

Abstract:

Objective: Nasopharyngeal carcinomas differ from other head and neck tumors. Patients have a higher rate of survival and thereby have a higher chance of presenting late toxicity, affecting their quality of life. We have tried to evaluate the most relevant late toxicities. Methods: We conducted a retrospective analysis in a series of 58 patients diagnosed with nasopharyngeal carcinoma between 1987 and 2014. The non-epithelial histological types were excluded from the study. We analyzed late toxicity and survival using SPSS version 19. Results: We included 58 patients, 93.1% of whom presented locally advanced disease at the time of diagnosis. The predominant subtype was found to be undifferentiated carcinoma. The treatment response rate was 91.2% (75.4% complete response and 15.8% partial response). The relapse rate was 35.1% (35% local relapse and 65% systemic relapse). The median disease-free survival was 150 months and the mean global survival was 224 months (168-279). The most frequent grade 3-4 toxicity during treatment was mucositis (50%), followed by nausea and vomiting (39%) and 37% of patients had delays in their treatment because of toxicity effects. The most relevant late toxicity was xerostomy (49%) and hypoacusia (26%). Conclusion: Nasopharyngeal carcinoma is usually diagnosed in a locally advanced stage. Treatment is based on chemotherapy and radiotherapy. Currently, there is large group of survivors, whose quality of life is severely affected by late toxicity.

Keywords: nasopharyngeal carcinoma; treatment; toxicity evaluation


Introduction

Nasopharyngeal carcinoma (NC) behaves differently than other head and neck tumors, not only from a clinical, but also from an epidemiological and geographical perspective. It is an infrequent tumor in Europe, where it has an incidence of about 1.1 per 100000 inhabitants/year. The areas that present the highest incidence are south China and south-east Asia with a reported incidence of 6.5 per 100000 inhabitants per year [1,2]. In Spain, the incidence rate oscillates between 0.3 and 0.7 cases per 100000 inhabitants per year [3].

It is three times more frequent in males and the median age at diagnosis is lower than that of other head and neck tumors [4].

Because of the anatomical location of the nasal cavity and the typically late presentation of symptoms, most cases are diagnosed at a locally advanced stage. Between 60-80% of patients are diagnosed with lymphatic node invasion and 5-10% of patients present with systemic metastasis [5].

Histologically, NC can be differentiated from other tumors in the same anatomical region using the classification proposed by the World Health Organization (WHO): differentiated squamous cell carcinoma (type 1), differentiated non-keratinizing carcinoma (type 2) and undifferentiated non-keratinizing carcinoma (type 3).

NC is a curable disease and it is considered to be more chemo- and radiosensitive than other head-and-neck tumors. The survival rate in adults can reach 76% after one year and 50% after 5 years [6,7]. Surgery, besides from establishing the diagnosis, only has a role in the treatment of important lymphatic invasion. There have been trials to optimize the treatment with curative intention, obtaining local and systemic disease control [8]. The combination of chemotherapy and radiotherapy in locally advanced stages has permitted an improvement of both local and systemic disease control, resulting in an increase of the 5-year survival rate. Thus, late toxicity effects are observed with increasing frequency, resulting in a decreasing quality of life.

With the goal of analyzing the clinical and pathological characteristics, therapeutic protocols and survival rate, with an important emphasis on late toxicity, we have designed a retrospective study including patients with NC in our hospital.

Materials and methods

Design

We conducted a retrospective descriptive study in a series of patients diagnosed with NC and treated in the University Hospital La Fe in Valencia, Spain, between 1987 and 2014. We excluded all non-epithelial histological types from the study.

We analyzed the clinical and pathological characteristics, the administered treatment, the produced toxicity (immediate and late), and the survival rate (disease-free and global).

Patients

We obtained a total of 58 patients, diagnosed with NC between 1987 and 2014. The patients were selected if they met the following criteria: have been diagnosed with NC between 1987 and 2014; have an epithelial histological type; have initiated a disease-specific treatment; not have been diagnosed with a psychiatric disorder nor being treated for one; not presenting degenerative, neurological or other diseases that could otherwise have an important effect on the patient during the study, thereby altering its results.

The initial study of all patients included a blood analysis with complete blood count, biochemical testing (albumin, kidney function, hepatic function, LDH), serology (HIV, HBV, HCV, EBV), chest radiography, CAT or MRI of the affected area.

The staging process was conducted following guidelines established by the International Union against Cancer (UICC) [9].

Data collection

Firstly, we revised the database of the Medical Oncology Department of our hospital, with the intent of finding those patients who met the established inclusion criteria. Afterwards, we revised the clinical history of the selected patients, proceeding with the analysis of the obtained information. The variables in this study were: sex; age; performance status; risk factors; initial symptoms (reason for encounter); histology and cellular differentiation; TNM classification at the time of diagnosis; existing metastasis and its location; first line treatment; cervical lymphadenectomy; response to the initial treatment; immediate treatment toxicity effects; the need for nasogastric tube or gastrostomy; treatment delays because of toxicity; disease progression and its location; duration of the response; posterior treatments and finally late toxicity and survival rate.

Statistical analysis

We made a descriptive analysis of general characteristics of the patients, paying specific attention to the toxicities that seem most relevant and affect the quality of life. Survival was analyzed by means of Kaplan-Meier curves. The program used for the statistical analysis was SPSS version 19.

Results

We included 58 patients with a male to female ratio of 3:1. Of all patients, 93.1% presented with locally advanced disease and the predominant subtype was undifferentiated carcinoma (79.3%). Only 6.9% of patients had metastasis at the time of diagnosis. The social-demographic and clinical characteristics are described in Table 1.

We found that 55.2% did not present any known risk factors and the principal reason for encounter was a palpable cervical tumor (36.2%).

The first line treatment has undergone some changes in the passing of the years, as is described in Table 2.


Table 1. Patients characteristics.

           Variables

Number (Percentage)

Patient number

58

Age, median (range)

50 years  (15-81 years)

Male/Female

42/16

Risk factors

    - No risk factors

    - Tobacco

    - Alcohol

    - Tobacco + alcohol

 

32 (55.2%)

16 (27.6%)

2 (3.4%)

8 (13.8%)

Reason for consultation

    - Palpable adenopathy

    - Rhinorrhea and nasal obstruction

    - Hypoacusia

    - Hypoacusia + nasal obstruction

    - Odynophagia

    - Aphonia

    - Otalgy

    - Others

    - Missing

 

31 (36.2%)

6 (10.3%)

4 (6.9%)

4 (6.9%)

2 (3.4%)

1 (1.7%)

1 (1.7%)

6 (10.3%)

13 (22.4%)

Histology

   - Differentiated squamous cell carcinoma

   - Non-keratinizing carcinoma

   -Undifferentiated non-keratinizing carcinoma

 

2 (3.4%)

10 (17.2%)

46 (79.3%)

Stage at diagnosis

   - Stage II

   - Stage III

   - Stage IV A

   - Stage IV B

   - Stage IV C

   - Missing

 

2 (3.4%)

11 (19%)

36 (62.1%)

3 (5.2%)

4 (6.9%)

2 (3.4%)

Metastasis at diagnosis

   - Without metastasis

   - Hepatic

   - Bone

   - Pulmonary

   - Pulmonary + hepatic + bone

 

54 (92.9%)

1 (1.7%)

1 (1.7%)

1 (1.7%)

1 (1.7%)

Performance status

    - 0

    - 1

    - 2

 

4 (6.9%)

48 (82.8%)

6 (10.3%)

 

                                                                                     



The technique utilized in radiotherapy has also been subject to advancements. Because of this fact, some of our patients were treated with a conventional 2D technique, while others were treated with Intensity Modulated Radiotherapy (IMRT), even though both groups had received the standard radiation dose.

The most commonly used chemotherapy schedules were: cisplatin (CDDP) concomitant with radiotherapy and followed by adjuvant CDDP-5-FU in 38.6% of cases, neoadjuvant 5-FU followed by CDDP and radiotherapy in 12.3% of cases and finally CDDP together with radiotherapy in 5.3% of cases.

The most frequent grade 3-4 toxicity during treatment was mucositis (50%), followed by nausea and vomiting (39%) and neutropenia (11.7%). A total of 17.2% of patients required the introduction of a nasogastric tube or a gastrostomy during the treatment and 37% of patients had delays in their treatment because of toxicity effects.

The most relevant late toxicity related to combination of CT/RT was xerostomy (49%) and hypoacusia (26%). We also found hypothyroidism (7%), neurotoxicity (7%), cutaneous toxicity (3.5%), secondary tumors (principally radiotherapy-induced sarcomas) (3.5%), odynophagia (2%) and others (3.5%). The quality of life of our patients was predominantly affected by xerostomy, hypoacusia and neurotoxicity, when not taking the secondary tumors into account.

The response rate following the RECIST criteria was 91.2% (75.4% complete response and 15.8% partial response). The relapse rate was 35.1% (35% local and 65% systemic). Pulmonary and bone metastasis were the most frequent systemic relapse locations.The second line treatment is detailed in Table 3.


Table 2. First line treatment in the series of patients.

First line treatment

Number (%)

CCRT followed by CT

22 (38.6%)

CT neoadjuvant followed by CCRT

7 (12.3%)

CCRT

3 (5.3%)

CT followed by RT

11 (19.3%)

RT followed by CT adjuvant

1 (1.8%)

Surgery (before other treatments)

5 (8.8%)

RT

8 (14%)

CT

5 (8.8 %)

CT: Chemotherapy; RT: Radiotherapy, CCRT: concomitant CT + RT.

 

Table 3. Second line treatment in the series of patients.

Second line treatment

Number

(%)

 

CT

 

12 (60%)

 

CT with RT (second time irradiation)

 

3 (15%)

 

Palliative care

 

4 (20%)

 

 CT: Chemotherapy; RT: Radiotherapy.



Multiple chemotherapy schedules were used in second line treatment: carboplatin-paclitaxel (15%), docetaxel (15%), CDDP-docetaxel-5-FU (10%), CDDP-5-FU (5%), CDDP-vinorelbine (10%), methotrexate (5%) and carboplatin-bleomycin-methotrexate (10%).

The median disease-free survival was 150 months and the mean global survival was 224 months (168-279). The median was not achieved (Figure 1 and 2).

Discussion

As in other published series, NC is most frequently diagnosed in men and at a younger age than that of other head and neck tumors. The most common histological subtype in our series was undifferentiated carcinoma and it has a tendency to be diagnosed at a locally advanced stage with frequent lymphatic invasion, which is reflected in our series as the most frequent reason for encounter (palpable cervical tumor in 36.2%).It is a very radiosensitive tumor with a 91.2% response rate and in 75.4% a complete response was achieved. Nevertheless, the relapse rate in our series was 35.1%, somewhat superior to other series that usually find a rate between 17-30% [10].

The treatment schedules of NC have been significantly modified in the last couple of years. It has evolved from a palliative treatment to a radical treatment with combined radiotherapy and chemotherapy. This has brought with it a significant increase in the survival rate of metastatic patients and has elevated the cure rate, with a significant increase in the long-time survival rate.

The most frequent toxicity effects during treatment administration were mucositis, nausea and vomiting in almost half of patients, resulting in 17.2% of them needing the introduction of a nasogastric tube or gastrostomy during the course of the treatment. There is a certain controversy about the need for nasogastric tube/gastrostomy before the initiation of the treatment. If we evaluate the previous data,

only a few patients required these invasive, sometimes aggressive, measures. Given that they are not free from complications, it would be reasonable to postpone their introduction until it is strictly necessary.

Because of the increase in long-time survivors we should start evaluating the late toxicity effects of the administered treatments in this patients, most of them at a young age at the time of initial treatment [11].


                                   

 

Figure 1. Overall survival. The mean global survival was 224 months                          Figure 2. Progression free survival. The median disease-free survival was 150 months.

 


The most relevant late toxicities were xerostomy (49%) and hypoacusia (26%), results similar to those found in other series of patients with head and neck tumors treated with chemotherapy/ radiotherapy and submitted to the quality of life questionnaire H&N35, where a dry mouth was the principal symptom decreasing quality of life.

Other side effects that could alter the functional capacity on the long term are hypothyroidism (7%), neurotoxicity (7%) and the development of secondary tumors, principally radiotherapy-induced sarcomas, which in some cases have no curative treatment options.

Recently, treatment options for NC have undergone some modifications, increasing the survival rate and the quality of life of these patients. Nevertheless, the long term effects of the treatments can in their turn deteriorate the quality of daily life for these patients. Therefore, when choosing the optimal treatment, we should not only consider the eradication of the disease, but also the reduction of any possible secondary effects. In order to achieve this goal we should listen to our patients, evaluate their toxicities and design comparative studies of late toxicity, permitting us to find the optimal treatment regimes, not only from a survival rate point of view, but also considering the quality of life on the long term.

Conclusion

Nasopharyngeal carcinoma is usually diagnosed in a locally advanced stage. Treatment is based on the use of chemotherapy and radiotherapy, obtaining a high response rate. Currently, there is large group of survivors, whose quality of life is severely affected by late toxicity.

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