Impact of combination therapy on disease free survival in hypopharynx cancer

Abstracts

OBJETIVO: Avaliar a sobrevida livre de doença nos tumores de hipofaringe submetidos ao tratamento operatório e à radioterapia pós-operatória. MÉTODOS: Estudo retrospectivo de 174 pacientes com distribuição, de acordo com o estádio clínico em: dois casos de estádio clínico I; quatro II; 46 III e 122 IV. Quanto ao gênero, 163 eram masculinos e 11 femininos, com idade média de 56 anos. Todos os casos foram submetidos à faringolaringectomia e realizados 206 esvaziamentos cervicais radicais e 16 seletivos. Cento seis pacientes foram submetidos à radioterapia pós-operatória, com dose média de 58,2 Gy. RESULTADOS: O exame histológico demonstrou dois casos de estádio clínico pT1, 15 pT2, 100 pT3 e 57 pT4. Quanto aos linfonodos, 25 pacientes apresentavam ausência de linfonodos comprometidos pela neoplasia (pN0) e 149 com linfonodos comprometidos pela neoplasia (pN+). A sobrevida livre de doença há cinco anos foi de 40% e a global de 28%. A sobrevida livre de doença há cinco anos foi de 75% no estádio clínico III versus 28% no IV, de acordo com o resultado do exame histológico. CONCLUSÃO: A manifestação inicial do carcinoma epidermóide de hipofaringe ocorre na fase avançada (estádios III e IV), com sobrevida livre de doença a cinco anos superior no estádio clínico III.

Carcinoma de células escamosas; Neoplasias; Hipofaringe; Sobrevivência livre de doença

ORIGINAL ARTICLE

^ISurgeon, Department of Head and Neck Surgery, Hospital de Heliopolis - Hosphel, São Paulo, SP, Brazil

^IIHead, Department of Head and Neck Surgery, Hospital de Heliopolis - Hosphel, São Paulo, SP, Brazil

Correspondence to

ABSTRACT

Objective: To evaluate the disease-free survival in hypopharyngeal tumors submitted to postoperative radiotherapy. Methods: we retrospectively studied 174 patients with the following distribution: two cases of stage I, four stage II, 46 stage III and 122 stage IV. Regarding gender, 163 were male and 11 female; mean age was 56 years. All patients underwent pharyngolaryngectomy; neck dissections were radical in 206 and selective in 16. One hundred six patients underwent postoperative radiotherapy, with a mean dose of 58.2 Gy. Results: Histological examination showed two cases of stage pT1, 15 stage pT2, 100 stage pT3 and 57 stage pT4. As for lymph nodes, 25 patients had no involvement (pN0); 149 presented with lymph node invasion (pN +). Five-year disease-free survival was 40% and the overall survival was 28%. According to the results of histological examination, five-year disease-free survival was 75% in clinical stage III versus 28% in IV. Conclusion: The initial manifestation of squamous cell carcinoma of the hypopharynx happens in advanced stages (III and IV), with superior five-year disease-free survival in clinical stage III.

Key words: Carcinoma, squamous cell. Neoplasms. Hypopharynx. Disease-free survival.

INTRODUCTION

Squamous cell carcinoma of the hypopharynx has initial clinical presentation in advanced clinical stages (III and IV in drinkers and smokers), even in developed countries, accounting for a five-year survival prognosis of 20 to 40%^1,2. The prognosis is related to age, poor and late presentation of signs and symptoms of the disease and aggressive behavior of locoregional recurrence in the first two years, evolving with distant metastasis at initial presentation or during the disease progression³. Distant metastasis is more likely to develop in advanced neoplastic disease and as first manifestation of failure of disease control, rates of 43% of distant metastases being found in patients with squamous cell carcinoma of the hypopharynx and locoregional control of the disease⁴.

Among the prognostic factors in squamous cell carcinoma of the hypopharynx, there is neoplastic involvement of lymph nodes. On the first visit to the specialist, 65% to 80% of patients have palpable metastatic nodes. In patients with clinically negative neck (N0), 30 to 40% will be discovered to have positive lymph nodes when submitted to histopathological examination^5-7.

Despite technological advances in the treatment and reconstruction in recent decades, the results in locoregional control of tumors of the hypopharynx showed no changes, especially in advanced stages. Tumors of initial clinical stages (I and II) have favorable results with surgery or radiotherapy alone, whereas clinically advanced ones (stages III and IV) showed better results with resection and associated postoperative radiotherapy¹.The overall survival in histology review ranged from 10% to 50%, with superior results in patients with early clinical stage disease (I and II). However, many of these patients present with advanced disease (III and IV)^2,7-13, in which there was no need for combination therapy. In a retrospective analysis of 94 patients initially treated with resection, disease-free survival at five years was 60% in all clinical stages, lymph node commitment being the main prognostic factor¹⁴.

This study aimed to evaluate the disease-free survival in patients with hypopharyngeal cancer undergoing surgical treatment and postoperative radiotherapy.

METHODS

We conducted a horizontal cohort study based on a retrospective analysis of 174 charts of patients with hypopharynx squamous cell carcinoma who had undergone initial surgical treatment with curative intent from January 1978 to December 2003.

Eligibility criteria were patients without prior cancer treatment and surgical treatment with curative intent. Exclusion criteria were the presence of simultaneous primary tumors, poor clinical conditions with KPS less than 70, unresectable tumors and indication of chemoradiotherapy in organ preservation protocols as initial therapy.

Patient's initial clinical stage was classified according to the TNM AJC UICC, 2002 (Table 1). For statistical analysis, we used the method of Kaplan-Meier.

RESULTS

Regarding the compromised anatomic subsite of the hypopharynx, three patients had a primary tumor with its epicenter on the posterior wall of the hypopharynx and 171 in the pyriform sinus. In 131 patients the tumors did not invade the midline, and in 43 cases this limit was exceeded (Table 2).

The primary tumor size (T) and the presence of lymph node involvement by the neoplasm (N) in the initial clinical presentation are outlined in Table 1. Regarding clinical stage (CS), two patients were stage I, four CS II, 46 CS III and 122 stage IV.

All patients underwent total laryngectomy or pharyngolaryngectomy when they had the primary tumor. When the laryngopharyngeal transit reconstruction was indicated, the pectoralis major musculocutaneous flap was used. One hundred and six (61%) patients underwent postoperative radiotherapy with linear or cobalt accelerator. The radiation dose ranged from 45 to 72Gy, with a mean dose of 52.8 Gy.

Mean follow-up was 31 months after the initial treatment. Regarding gender, 163 were male and 11 female. The average age was 56 years, ranging from 36 to 80.

As for the cervical approach, 222 neck dissections were performed, of which 206 were radical or modified (levels I to V) and the remaining 16 were selective (levels I to III). Of these 222 neck dissections, 48 were bilateral, comprising radical/modified (stages I to V) and selective (levels I to III) ones. Ten patients died within 30 days after surgery due to clinical complications, such as pneumonia, acute myocardial infarction and stroke.

In histopathological examinations, as the primary tumor, two patients were pT1, 15 were pT2, 100 were pT3 and 57 were pT4. Among the 34 N0 patients, 14 (41.2%) were false-negative (pN +) and from the 140 N + patients, seven (5%) were false positive (pN0). Therefore, in relation to lymph node, 27 patients had no lymph nodes involved by cancer (pN0), whereas 149 were node positive (pN +).

The overall survival at five years was 28%. Figure 1 shows the curve of five-year disease-free survival for these patients.

Considering lymph node status on histology, disease-free survival at five years was illustrated in Figure 2 (p=0,001).

As for the clinical stage of the 164 patients with follow-up, two were stage I, three were II, 22 were III and 137 were IV. Five-year disease-free survival is shown in Figure 3, considering the clinical and pathological disease stage (p=0.0004).

Thirty-eight (21.8%) patients referred to postoperative radiotherapy were not submitted to it due to complications in the surgical wound and poor socioeconomic conditions, losing the time frame considered ideal to irradiation.

With regard to recurrences, we observed 15 isolated local recurrences, 15 regional isolated, 18 isolated distant metastases, 13 locoregional and nine locoregional and distant (Figure 4). Apart from these, six patients developed peri-tracheostomy recurrences and one patient developed lymph node recurrence in the retropharyngeal space. We performed 12 rescue surgeries, ten of which for regional recurrences and two for isolated locoregional recurrences. Six patients underwent postoperative radiotherapy. Seven patients were treated with salvage radiotherapy, three for isolated regional recurrences and three for locoregional ones. Only one patient with peri-tracheostomy recurrence underwent resection and radiotherapy. The other patients with locoregional recurrences were directly referred to palliative care. Distant metastasis occurred in 27 cases, and the most frequent sites of involvement were: lung, brain, skin and axilla. Fourteen patients developed a second primary tumor, two in the head and neck, such as the mouth floor and tongue edge.

DISCUSSION

When treating squamous cell carcinoma of the hypopharynx, one should consider the preservation of voice, swallowing without aspiration and impact of these functions to the patient's quality of life. In this context, early clinical stage diseases (I and II) showed good survival and functional outcome following surgical treatment or radiotherapy as the initial treatment^14,15. Moreover, the disease in advanced clinical stages (III and IV) has encouraging results with the combination of resection with radiotherapy in addition to being the standard treatment at this point¹⁶.

The present study demonstrated a high rate of 21.8% of patients with advanced disease without radiotherapy after surgery. Sixty-eight patients were not irradiated in the initial treatment. Ten cases died within 30 days after surgery and 58 patients did not undergo postoperative irradiation in the absence of histopathological criteria established in the literature for complementation with postoperative radiotherapy, such as lymph node involved and capsular rupture, margin compromised by neoplasia, pT4 tumors and perineural invasion. Postoperative complications caused the considered optimal period for adjuvant radiotherapy to be exceeded, such as wound infection and necrosis, wide pharyngo-cutaneous fistulae and lack of adherence to treatment, usually by poor socioeconomic conditions.

Still, during the 20 years included in the study, the wound complication rates suffered interference, such as the surgeon formation time (learning curve), developments in the preoperative prophylaxis of infections and the emergence of wide-spectrum antibiotics and measures of asepsis and antisepsis. However, the biological behavior of these tumors deserves special attention, as it determines an insidious onset and diagnosis in advanced stages.

The absence of postoperative radiotherapy is associated with lower rates of overall survival and disease-free survival. Comparing the results of this study with a series of 104 patients initially treated surgically, 80% were in advanced stage (T3 and T4), 62% had cervical metastases and 66% underwent postoperative radiotherapy. Locoregional recurrences occurred in 38 (37%) patients, with 47% overall survival and 62% five-year disease-free survival¹⁷.

The results are corroborated in a retrospective population study conducted in Canada with patients with squamous cell carcinoma of the hypopharynx, where the primary tumor size was a significant prognostic factor for survival along with lymph node status¹⁸.

Differences in disease-free survival in clinical stages III and IV observed in this study can be attributed to the presence of T4 tumors of greater size and degree of infiltration, causing no detectable subclinical disease.

Some authors demonstrated that the failure of initial treatment was related to regional recurrence and distant metastasis, with better rates of disease local control^17,19. In that series, similar and superior results were shown for hematogenous metastases, with 26% of patients with distant dissemination.

Lymph node status is an independent prognostic factor in several series, which unanimously show, by univariate and multivariate analyses, the worst results of disease-free survival in the presence of lymph node involvement^14,19.20. We demonstrated similar results on five-year disease-free survival in patients with tumors of the hypopharynx in the presence of lymph node involvement by cancer, exceeding 70% in pN (0) versus 30% in pN (+) cases.

Depending on the type of initial therapy, the rates of local disease control in the literature are variable, such as survival of 16% in initial tumors and 18% in advanced tumors with association of resection and complementary radiotherapy²¹. Discordant results were observed in this study, local recurrences presenting rates around 53%. Local failure can be related to the prevalence of advanced tumors (T3 and T4) and the absence of additional postoperative radiotherapy in 21.8% of induviduals. The isolated use of radiotherapy in the primary tumor resulted in a survival rate of 6%¹⁶. Although this study did not focus on the initial radiotherapy or chemoradiotherapy for tumors of the hypopharynx, the worst results of organ preservation are found in advanced tumors with deep infiltration and involvement of the neck soft tissues²².

The guidelines of our department advocate surgical treatment for tumors of the hypopharynx in association with postoperative radiotherapy. Disease-free survival after initial surgical treatment with or without postoperative radiotherapy was 40% and 96.5% of the tumors presented as advanced disease at the time of manifestation (clinical stages III and IV).

In the face of a disease with advanced initial manifestation, clinical-pathological stages III and IV represent 91.4% of the histopathology findings. When comparing the curves of disease-free survival between these two clinical stages, this study showed 75% disease-free survival in stage III and 30% in stage IV. This difference is related to primary tumor size (T3 and T4), given that local recurrence alone is rarely capable of salvage therapy, being the main cause of failure in controlling the disease.

The rate of distant metastasis is higher in squamous cell carcinoma of the hypopharynx, fact related to the presence of disease in an advanced clinical stage at the time of diagnosis²¹. Distant metastasis of hypopharynx neoplasia is also related to the first clinical manifestation of failure in controlling the disease, with rates of 16% and 20%^23,24. Our study showed similar data, with detection of 15.5% of distant metastasis during follow-up; in 66.7% of cases distant metastasis was the first manifestation of disease recurrence.

Therapeutic planning in hypopharynx cancer should be preceded by careful assessment of imaging methods, such as Pet-CT, in all clinical stages, focusing on the detection of subclinical disease.

Squamous cell carcinoma of the hypopharynx has its initial manifestation predominantly in advanced clinical stages III and IV (96.5%), with findings of five-year disease-free survival higher in patients with clinical stage III and no lymph node involvement on histological examination.

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Impact of combination therapy on disease free survival in hypopharynx cancer

Helma Maria Chedid^I; Sergio Altino Franzi^I; Abrão Rapoport, ECBC-SP^I; Otávio Alberto Curioni, TCBC-SP^II

Publication Dates

• Publication in this collection
  04 Feb 2011
• Date of issue
  Dec 2010

History

• Received
  03 Oct 2009
• Accepted
  14 Dec 2009