Advances in lung cancer management

S Y So 蘇淳養

HK Pract 2003;25:300-306

Summary

Lung cancer is still the most common lethal cancer in both males and females in Hong Kong, as the majority of patients present late with advanced disease. It is now possible to make an early diagnosis of lung cancer with low-dose high-resolution computerised tomography of the chest or fluorescent bronchoscopy. Whether or not these new methods are suitable for the screening of susceptible persons is still under investigation. The introduction of metabolic scanning - positron emission tomography (PET) - has much improved the imaging for lung cancer staging. When combined with computerised tomography (PET-CT), the metabolic abnormality is better defined anatomically. Surgery remains the treatment of choice for early cancers (stage I & II). For tumours with mediastinal lymphadenopathy (stage IIIA), pre-operative chemotherapy is promising, as it may reduce the tumour bulk and make later resection possible. For locally advanced cancers (stage IIIB), concurrent chemo-radiotherapy is better than radiotherapy alone in terms of survival. Modern radiotherapy with 3-D conformal or intensity modulated techniques is associated with greater efficacy and fewer side effects. For metastatic disease (stage IV), platinum-based combination chemotherapy gives better survival and quality of life than supportive care alone. Side effects from chemotherapy are more acceptable now. The nihilism for chemotherapy should be abandoned, especially for the elderly. The advent of molecular targeted therapy has further enhanced the therapeutic armamentarium.

摘要

肺癌仍然是香港男性及女性最常見的致命癌病，因為大多數的病人，就醫時已屬病情後期。 現在使用低輻射高解像度的電腦掃描或螢光氣管內窺鏡可以診斷出較早期的肺癌。 目前正在研究是否可以利用此類技術為高危人仕進行普查。引入代謝掃描 — PET（正電子發射X線斷層攝影術），可以大大提高肺癌分期的評估能力。配合CT（電腦素描）， 不正常的新陳代謝部分的解剖學位置更能更有效的顯示出來。早期的癌症（第一期及第二期）， 外科手術是首選的治療方法。如果已蔓延至縱隔淋巴腺的肺癌（第三期甲），術前化療可以為病人帶來希望， 因為化學療法能夠使腫瘤縮小，進而做手術切除。局部蔓延的癌病（第三期乙）， 同時間使用化療和電療比單一電療更能提高病人的生存率。現今的電療方法使用三維或強度調節的技術， 比起過往的方法更有效而副作用更少。已擴散的肺癌（第四期）， 以白金為基礎的綜合化學療法比單純支援性療法更有助提升患者的生存率及生活質素。 現在化學療法的副作用已較為容易接受。應當拋棄否定化學療法作用的虛無主義，尤其是對於年長的病人， 應當考慮給予適當。以分子為目標的新療法，也為治療帶來新的動力。

Introduction

Lung cancer is a major health problem. It is the most common cancer in men in Hong Kong. In women, it is second only to breast cancer in incidence; however, it is the number one cancer killer for both men and women. In 1999, 3168 patients died as a result of lung cancer in Hong Kong.¹ The expected 5-year survival rate for all patients in whom lung cancer is diagnosed is 15%, compared with 61% for colon cancer, 86% for breast cancer and 96% for prostate cancer.²

Although a 15% 5-year survival rate is still dismal, it is better when compared to the survival rate of 8% seen in the 1960s. The improvement in survival is mainly due to better therapeutic measures, as 82% of patients still present late² and there is as yet, no report that early detection of lung cancer by screening can improve survival.³ The better survival has shifted the nihilism associated with lung cancer treatment into a guarded optimism.

As over 90% of lung cancers are non-small cell lung cancer (NSCLC), the following discussion will be confined to this histological type. Among the NSCLC, adenocarcinoma has surpassed squamous cell carcinoma as the leading lung cancer for both men and women in Hong Kong.¹

Risk factors for lung cancer

A recent study found that smoking is still the most important risk factor associated with lung cancer in Hong Kong, though the attributable risk is lower than that in early 1980s - 45.8% in men and 6.2% in women.⁴ Environmental tobacco smoke, but not incense burning or frying pan fumes, has emerged as a risk factor for both sexes.⁴

Early detection

1. Low-dose high resolution CT scan of thorax (HRCT)

A cure is possible if NSCLC is detected early enough to be resected surgically. Hence study on screening for early lung cancer using serial chest x-ray (CXR) with or without sputum examination has been conducted; however there is no survival benefit demonstrated with such screening.³

The introduction of low-dose computerised tomography (LDCT) of the thorax has rekindled interest in cancer screening. The radiation dose of LDCT is equivalent to that of 2 to 4 CXR only, so that serial screening poses minimal hazard. Two large observation studies using LDCT have found more early lung cancers than CXR. However, there is as yet no long-term survival data for these 'screening-detected' cancers. The benefit from LDCT remains uncertain. Moreover, LDCT is so sensitive that it picks up many non-calcified lung nodules that may turn out to be benign by biopsy. It then creates unnecessary anxiety among people being screened. It may also detect cancers that may remain indolent for years, so that their surgical removal may not improve outcome. Current guidelines recommend that for individuals without symptoms or previous history of cancer, serial LDCT is not justified. For chronic smokers, serial LDCT may be considered only in the setting of a clinical trial until more data are available.³

2. Fluorescent bronchoscopy

Another new technique to detect early lung cancer is laser-induced fluorescent endoscopy (LIFE). Blue light instead of white light is used during the bronchoscopy and pre-invasive squamous dysplasia or carcinoma-in-situ will be identified as they emit less green fluorescence.

Screening with LIFE has one major problem - there is not enough data on how such early carcinomas should be managed, as not all of them will progress to aggressive malignancy; some may regress spontaneously. Furthermore, false positive results may occur and LIFE cannot detect other centrally situated cancers such as small cell and adenocarcinoma.

Diagnosis of primary tumour

Diagnosis of NSCLC is not difficult when a patient presents with respiratory symptoms and an abnormal CXR. For a central lesion, sputum cytology and bronchoscopy will be helpful. For a peripheral tumour, percutaneous fine needle biopsy of the mass under CT guidance is preferred. If there is a pleural effusion, repeated pleural fluid cytology should be tried before thoracoscopy.

For distant metastasis, fine needle biopsy of the extra-thoracic site is recommended if it is technically accessible.

Evaluation of spread of tumour (Staging)

Staging of lung cancer not only provides prognostic information on survival, but also guides decision-making in choosing the appropriate treatment modalities.

1. New staging system for lung cancer (Table 1)

The staging classification for NSCLC was revised recently in an attempt to refine the placement of patients into strategies with similar survival rates and therapeutic options.⁵ For example, some tumours previously staged as IIIA are now re-categorised as IIB and become resectable.



2. Non-invasive staging with imaging

Determination of mediastinal lymph node involvement is crucial in deciding resectability of lung cancer.

CT scan of the thorax can be used to evaluate lymph node metastasis on the basis of node size i.e.>1cm in diameter. Pooled data showed CT scan had a sensitivity of 57% and specificity of 82% for mediastinal lymph node metastasis.⁶

The introduction of positron emission tomography (PET) has facilitated the staging of lung cancer. PET scan measures the metabolic activity of the lesion. Malignant cells tend to take up and retain more of the injected 18-fluorodeoxyglucose (FDG). As 18-fluorine decays, it emits positrons that are then scanned. PET scan has been shown to be much more sensitive and specific in detecting malignant mediastinal lymph node involvement than CT scan: pooled data showed PET scan has a sensitivity of 84% and a specificity of 89%.⁶ When PET is performed simultaneously with CT (fusion scan), the anatomical area of high metabolic activity is better defined. PET-CT scan has a sensitivity up to 93% and a specificity up to 95%.⁶ However, PET scans may give false positives in tuberculosis.

Whole body PET scan has the additional advantage of detecting extra-thoracic spread of cancer and picks up metastases not found by CT scan in up to 20% of cases.⁶

3. Invasive staging for mediastinal lymphadenopathy

Mediastinoscopy and mediastinostomy have long been employed for staging mediastinal lymphadenopathy. Recently, several techniques have been introduced: video-assisted thoracoscopy, transbronchial needle aspiration (TBNA) via bronchoscopy, transthoracic needle aspiration (TTNA) under CT or ultrasound guidance, and endoscopic ultrasound with fine needle aspiration (EUS-NA) through the bronchoscope or oesophagoscope.

When the primary objective is to confirm a diagnosis of NSCLC with extensive mediastinal infiltration, TTNA and EUS-NA are the procedures of choice because of high sensitivity (90%) and low morbidity. TBNA is an alternative, but it has a lower sensitivity (70%).⁷

When the primary objective is to confirm that there is no involvement of mediastinal lymph nodes in preparation for surgery, mediastinoscopy remains the procedure of choice, as it can sample most of the mediastinal lymph nodes.⁷

Treatment

1. Treatment of Operable (Stage I, II) NSCLC
1. Medically fit patients

Full resection (lobectomy or pneumonectomy) rather than limited resection (wedge resection or segmentectomy) should always be attempted. There is enthusiasm for minimally invasive thoracoscopic resection as it may be associated with less post-operative pain; however there is no proof yet that it is better than traditional thoracotomy.⁸ Full mediastinal lymph node dissection is theoretically attractive, but it has not been associated with better therapeutic benefit.⁸ The routine use of post-operative chemotherapy is not recommended; however recent phase II data suggest that pre-operative chemotherapy may deal with occult micro-metastasis and improve survival.⁸

The use of post-operative radiotherapy may be considered if the resection margin is positive for tumour cells, or there is hilar lymphadenopathy at operation, or there is incomplete resection of chest wall or mediastinal invasion. It may decrease local recurrence, but it does not affect survival.⁸ Recent data suggest that post-operative chemotherapy may enhance survival.⁹

2. Medically unfit patients

Curative radiotherapy should be considered.

2. Treatment of Potentially Operable (Stage IIIA) NSCLC

These are locally advanced lung cancers with mediastinal lymphadenopathy (N₂), making complete resection difficult. In recent years, there have been attempts to increase their resectability with pre-operative induction chemotherapy. This, in theory, may decrease tumour size to allow more ready resection, decrease micro-metastasis, decrease surgical seeding and increase patient acceptance. Preliminary results show that induction chemotherapy does not cause a delay in primary tumour control and may actually increase survival compared with surgery alone,¹⁰ although the final verdict has to come from the results of large, randomised phase III trials.

3. Treatment of Locally Advanced (Stage IIIB) NSCLC

These are unresectable tumours. For patients with good performance status and minimal weight loss, concurrent chemo-radiotherapy has resulted in better survival than radiotherapy alone. Multiple daily fractions of radiotherapy have not resulted in better survival than traditional standard fractionation once daily.¹¹

4. Treatment of Metastatic (Stage IV) NSCLC

The efficacy of chemotherapy for NSCLC was questioned until a meta-analysis involving 9382 patients in 1995 demonstrated unequivocally a survival benefit with platinum-based combination chemotherapy.¹² Compared with best supportive care alone, chemotherapy improved one-year survival by 10%. The newer agents such as paclitaxel, doxetaxel, gemcitabine and vinorelbine are a little more active, with extension of median survival, to 10 months and, 1-year survival, to 40%.

At least 7 studies have shown chemotherapy can improve symptoms such as cough, haemoptysis and weight loss.¹² Eight randomised trials revealed meaningful improvement in quality of life score with chemotherapy.¹² Interestingly a partial or complete tumour response is not essential for symptomatic relief.

Concerns about the side effects of chemotherapy have been ameliorated with the introduction of new cytotoxic drugs and anti-emetics. Patients are now more prepared to accept some toxicity in return for significant palliation of symptoms and modest extension of life.

Chemotherapy is usually offered to patients with good performance status or with minimal mobility problems. Some trials have demonstrated great symptomatic relief with chemotherapy even for patients with significant impairment of mobility. For example, one of my patients with diffuse lung metastases had severe dyspnoea and marked hypoxaemia. Symptoms improved dramatically after chemotherapy and the patient was even able to resume working (Figure 1). The nihilism for chemotherapy should be abandoned.

Justification for treatment of the fit elderly

The majority of lung cancer patients are elderly (70 years). Age alone has no prognostic significance in lung cancer.

No active treatment was offered to them in the past. Current data suggest that they tolerate surgery, radiotherapy and chemotherapy equally as well as the young, provided that they have good performance status. Post-treatment survival and symptoms control is satisfactory.^14,15 The fit elderly should not be denied active treatment.

Promising new molecular targeted therapy

Drugs for cancer chemotherapy are broad spectrum in action. There are now new, narrow-spectrum, agents which target tumour cells at specific molecular sites, so as to inhibit tumour growth, block new blood vessel formation into tumour, or abolish the 'immortality' of abnormal cells.

The first to be marketed is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor called gefinitib (Iressa). Gefinitib, used alone as second or third line salvage therapy for patients with NSCLC refractory to platins or taxols, will give median survival of 6-7 months. More importantly it relieves symptoms quickly within 7-10 days in 40% of patients.¹⁶ Side effects include skin rash, diarrhoea and rarely interstitial pneumonitis.

Gefinitab has been combined with concurrent chemotherapy, and there is no additional survival benefit. The reasons are not clear. Chemotherapy may have altered EGFR.

Trials are being conducted to determine whether EGFR inhibitor may act synergistically with radiotherapy. EGFR inhibitor may have a role as first line therapy in the elderly in the future, as it is easily given by mouth daily.

New methods of radiotherapy

1. 3D-Conformal Radiotherapy

This utilises CT scan to digitally reconstruct the 3-dimensional volumetric definition of the tumour and the anatomy of critical organs. The calculation of the radiation dose is conducted on the whole treated volume and not on the transverse surface of the treated volume as in conventional radiotherapy. 3D Conformal Radiotherapy is applied in situations that require higher doses (20-30%), thereby reducing the risk of complications

2. Intensity modulated radiotherapy (IMRT)

Traditional radiotherapy utilises uniform beams of radiation, producing a uniform distribution of dose throughout the irradiated volume. This ensures the target is adequately covered, but does nothing to avoid critical structures. With IMRT, the beams of radiation are made to be intentionally non-uniform. In this way the dose distribution can be exquisitely shaped to minimise radiation to surrounding structures. This provides for optimal chance of cure while simultaneously minimising any risk of complication.

Conclusion

Lung cancer is a huge problem worldwide, which could largerly be prevented if anti-smoking measures were to become more rigorous.

Some progress has been made in the early detection and management of patients with both early and advanced lung cancers. Practitioners should adopt a more positive attitude in disease control and symptomatic palliation, especially for the elderly.

Key messages

1. Lung cancer is still the most common lethal cancer in both males and females in Hong Kong.
2. Screening for early lung cancer with low-dose high-resolution computerised tomography of the chest or fluorescent bronchoscopy is still controversial.
3. The introduction of metabolic scanning - positron emission tomography (PET) - has much improved the imaging for lung cancer staging.
4. Surgery remains the treatment of choice for early (stage I & II) non-small cell lung cancers (NSCLC).
5. For NSCLC with mediastinal lymphadenopathy (stage IIIA), pre-operative chemotherapy is promising.
6. For locally advanced NSCLC (stage IIIB), concurrent chemo-radiotherapy is better than radiotherapy alone in terms of survival.
7. For metastatic NSCLC (stage IV), platinum-based combination chemotherapy gives better survival and quality of life than supportive care alone. Side effects from chemotherapy are more acceptable than they used to be.
8. The advent of molecular targeted therapy has further enhanced the therapeutic armamentarium.