Chapter 14
Early cancer therapies
Marta Díez-Ferrer1, Cristina Gutierrez2 and Antoni Rosell1
1Bronchoscopy Unit, Dept of Respiratory Medicine, Hospital Universitari de Bellvitge, Universitat de Barcelona, IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain. 2Brachytherapy Unit, Dept of Radiotherapy and Oncology, Institut Català d’Oncologia, L’Hospitalet de Llobregat, Barcelona, Spain.
Correspondence: Antoni Rosell, Bronchoscopy Unit, Dept of Respiratory Medicine, Hospital Universitari de Bellvitge, Universitat de Barcelona, IDIBELL, Feixa Llarga s/n, L’Hospitalet de Llobregat, 08907 Barcelona, Spain. E-mail: arosell@bellvitgehospital.cat
Bronchoscopic therapies for early lung cancer have shown very promising results but strong evidence comparing available treatments is still lacking. Endobronchial therapies have been attempted in proximal lesions, including Nd-YAG laser therapy, electrocautery, cryotherapy, brachytherapy, APC and PDT. Approaching the lung periphery is still challenging and peripheral lesions in patients who cannot undergo surgery often have to be managed using a CT-guided percutaneous approach. Percutaneous techniques include laser ablation, RFA, microwave ablation, cryotherapy and PDT. Newer bronchoscopically guided and navigational technologies may be able to deliver these therapies effectively to peripheral lesions in the near future with fewer complications than the percutaneous approach.
Cite as: Díez-Ferrer M, Gutierrez C, Rosell A. Early cancer therapies. In: Herth FJF, Shah PL, Gompelmann D, eds. Interventional Pulmonology (ERS Monograph). Sheffield, European Respiratory Society, 2017; pp. 210–223 [https://doi.org/10.1183/2312508X.10010817].
Newer therapies for early lung cancer have emerged and should be made available when surgery and radiotherapy are contraindicated, e.g. in patients in whom the amount of normal tissue that has to be removed or denaturalised is too large according to their lung function, those with unresectable central tumours or in cases where further intervention might be needed due to the presence of metachronous lesions. Therefore, the use of bronchoscopic therapies in the management of lung cancer that is limited to the airways has shed new light on the management of early lung cancer.
Several techniques (many of which are covered elsewhere in this Monograph [1]) are available to treat endoluminal superficial lesions, including laser therapy, electrocautery, APC, PDT, cryotherapy and brachytherapy. The curative potential of all these therapies has been demonstrated, as all of them are able to effectively destroy tumours of up to a depth of 5 mm in central early lung cancer. However, positioning endoscopic therapies in the management of early lung cancer remains challenging. The heterogeneity of the inclusion criteria in the reported studies as well as the difficulty of conducting randomised controlled trials comparing natural outcomes of early stage superficial lesions with the different therapies are the main reasons for the limited weight of current evidence.
The definition of early lung cancer used in the studies of bronchoscopic therapies does not correspond exactly to the current definitions of the TNM (tumour, node and metastasis) classification and differs among authors. In 1989, NAGAMOTO et al. [2] observed that squamous cell carcinoma (SCC) ≤3 mm thick and with a longitudinal extension <20 mm was associated with no nodal involvement. In 1999, KONAKA et al. [3] suggested that hypertrophic lesions (i.e. those with only superficial thickening of the epithelium) <1 cm2 in surface area are either carcinoma in situ (CIS) or micro-invasive tumours within the muscle layer, while nodular and polypoid lesions ≥1 cm2 in surface area are more likely to be invasive beyond the cartilaginous layer. Accordingly, in 2003, MATHUR et al. [4] defined early stage cancer as radiographically occult SCC that is endoscopically superficial, <2 cm2 in surface area with clearly visible margins and not invading beyond the bronchial cartilage. Later, in 2010, the Japan Lung Cancer Society defined the bronchoscopic criteria of central-type early stage lung cancer as that located subsegmentally or more proximally, <2 cm2 in surface area with bronchoscopically recognisable margins and proven SCC [5]. However, evidence shows that pre-invasive bronchial lesions should also be detected and treated due to their higher risk for cancer [6, 7].
The current edition of the International Association for the Study of Lung Cancer TNM classification incorporates new definitions in the early stages, including some special situations [8]. Superficial spreading tumours in the central airways are those confined to the tracheal or bronchial wall regardless of size and location, and are labelled T1a ss. CIS (classified as Tis) now includes both SCC in situ (or squamous dysplasia) and adenocarcinoma in situ (AIS, which is localised, ≤3 cm and shows pure lepidic growth, lacking stromal, vascular, alveolar space or pleural invasion). Minimally invasive adenocarcinoma is classified as T1a(mi) and corresponds to solitary adenocarcinoma ≤3 cm with a predominantly lepidic pattern and ≤0.5 cm invasion. The invasive component is defined as a histological type other than lepidic or tumour cells infiltrating myofibroblastic stroma. In our setting, it is important to note that examination of small biopsy specimens cannot exclude or quantify invasive components for AIS and T1a(mi), respectively. Although there can be a high suspicion of AIS with biopsies with a pure lepidic pattern, together with a CT correlation of the ground-glass component, AIS and T1a(mi) require examination of the entire resection specimen [8, 9].
The accuracy of the techniques used for diagnosing early lung cancer is crucial for defining the lesions suitable for endobronchial therapy. High-definition bronchoscopy, AFB and NBI have been used for defining the margins of the lesion, the latter having a higher specificity [10]. To evaluate the shallowness of the tumour, radial EBUS and OCT have been used [11]. The combination of AFB and OCT has also shown good results for both the detection and characterisation of pre-malignant lesions of the central airways [12]. Thin-section CT (≤1 mm) and PET-CT might also be useful in the evaluation of pre-malignant lesions [13, 14]. A comprehensive review of early stage cancer diagnostic techniques can be found elsewhere in this Monograph [15].
Treatment success is directly dependent on lesion accessibility and the ability to correctly delineate the margins and shallowness of the lesions [16]. Given the accumulated evidence, it is logical to think that pre-malignant lesions and those limited to the tracheal and bronchial wall (i.e. T1a ss tumours) might be suitable for endoscopic curative treatments, granted that lesion margins and shallowness are correctly delineated. Once the limits of the lesion are defined, and according to current evidence, choosing one technique over another depends mainly on the expertise of the bronchoscopist and the availability of the therapy. However, some of the practical characteristics of each technique should be considered.
Finally, due to the high risk of primary and second primary lung cancer in patients with pre-malignant lesions, as well as cancer progression and recurrence, follow-up is another key issue to be determined. In this sense, bimodal surveillance with AFB and CT has shown the highest detection rate, which was 34% in a 10-year follow-up [6]. However, more efficient strategies should be explored.
Here, we review the available bronchoscopic therapies for the management of endobronchial early cancer limited to the proximal airways (table 1). We will also briefly present the percutaneous therapies that are currently available for the management of peripheral lung cancer (table 2).
Table 1. Endobronchial therapies for early lung cancer
Therapy | Principle | Depth | Main risks | Considerations |
|---|---|---|---|---|
Laser | Thermal ablation with laser light | Up to 10 mm (but variable) | Airway perforation, haemorrhage, airway fire, respiratory failure | As for thermal therapies# |
Electrocautery | Thermal ablation through electric current flow | Up to 10 mm (but variable) | Airway perforation, haemorrhage, airway fire, respiratory failure | As for thermal therapies#; caution with pacemakers; cheaper than laser therapy |
APC | Thermal ablation with electric current through argon gas | 2–3 mm | Airway fire, respiratory failure | As for thermal therapies#; caution with pacemakers |
PDT | Nonthermal ablation with light in previously photosensitised tissues | 3 mm | Respiratory failure | Produces intense photosensitivity; delayed results and need for repeat bronchoscopy |
Cryotherapy | Rapid tissue freezing causing cell death and ischaemic necrosis | 3 mm | Respiratory failure | Delayed results |
Brachytherapy | Radiation therapy applied directly to tumour through endobronchial catheter | Variable | Ulcers, fibrosis, stenosis, haemoptysis | Accumulative radiation dose; high complexity and need for multidisciplinary team |
#: thermal therapies should be applied with an oxygen concentration <30–40% due to ignition risk and rigid bronchoscopy considered, although laryngeal masks can be used and are safer than ETTs. | ||||
Table 2. Percutaneous treatments for peripheral pulmonary lesions
Therapy | Application | Principle | Main risks |
|---|---|---|---|
Laser | Nd-YAG laser applied through outer sheath | Thermal ablation with laser light | Pneumothorax |
RFA | RFA applied through an electrode placed in the tumour | Thermal ablation with kinetic energy | Pneumothorax, pleuritic chest pain, haemoptysis, pleural effusion |
Microwave | Microwave energy applied through a needle placed in the tumour | Thermal ablation with kinetic energy | Pneumothorax |
Cryotherapy | Cryoablation probe placed in the tumour | Ablation through tissue freezing | Pneumothorax, bleeding |
PDT | PDT applied through catheters placed in the tumour | Thermal ablation with light in previously photosensitised tissues | Pneumothorax |
Laser therapy
“Laser” is an acronym for “light amplification by stimulated emission of radiation”. Briefly, stimulation of an active substance produces photons that are reflected inside the laser cavity, producing new photons which make up the laser beam. Laser light energy is used for thermal tissue ablation (figure 1). The wavelength of a particular laser is determined by the stimulated substance. The power settings of the laser machine (measured in watts) can also be regulated. Finally, the exposure time or so-called laser energy (measured in joules), the density of the impact surface, the distance from the laser fibre to the target, the colour of the tissue surface and the angle of incidence also determine the effect of the laser beam on the tissue. This effect can be relatively superficial and is then used for coagulation; however, when higher temperatures are obtained, a deeper resection and vapourisation effect is produced on the tissue [17]. Although laser therapy is a very precise technique, there is also some degree of delayed effect of the laser on the surrounding tissues due to heat energy absorption [18]. Of all the lasers, the Nd-YAG (neodymium-doped yttrium aluminium garnet) laser is the most commonly used due to its resection and vapourisation properties. The Nd-YAG laser emits in the infrared range at 1064 nm and therefore a red helium–neon beam is used to mark the area of application that would otherwise be invisible.
Figure 1. Nd-YAG laser application on a tumour.
Laser therapies are most commonly applied using a rigid bronchoscope under general anaesthesia, either directly through the rigid bronchoscope or through the working channel of a flexible bronchoscope. Laser therapy is mainly indicated in the acute treatment of life-threatening central airway obstructions (CAOs), mainly for the palliation of symptoms derived from a malignant infiltration of the main airways, although it can also be used in benign stenosis. However, there are some reports on the use of laser therapy for the management of early lung cancer that is limited to the inner lumen of the proximal airways. CAVALIERE et al. [19] investigated the use of Nd-YAG laser therapy to treat 19 CIS over a 10-year period. They reported no recurrence of CIS in any case, although they only specified a follow-up period in one case, which was of 4 years [19]. A number of other cases have been reported, including an epithelial–myoepithelial carcinoma with a PET-CT negative control after treatment [20] and a case of multiple poorly differentiated SCC lesions treated with an Nd-YAG laser with no recurrence after a 1-year follow-up [21]. VONK-NOORDEGRAAF et al. [22] also reported a case that was successfully treated with Nd-YAG laser therapy, although they did not specify histology or the follow-up period, which was at least 2 years. Finally, VAN BOXEM et al. [23] reported the successful treatment of three out of four endoluminal typical carcinoids.
Electrocautery
Electrocautery uses an electric current to produce thermal ablation of the tissues (figure 2). The effects of electrocautery on tissue include coagulation, vapourisation and fulguration (according to the nature of the lesion); tissue penetration is determined by the adjusted frequency of the waveform and the peak voltage. As with laser therapy, there is some degree of delayed effect of electrocautery on the surrounding tissues due to heat energy absorption. Electrocautery is most often applied with unipolar electrodes through the working channel of a flexible bronchoscope and under conscious sedation, although rigid probes with several configurations exist that can be used through rigid bronchoscopes under general anaesthesia. The probe is placed in contact with the tissue in order to produce the desired effect. It is important for a neutral plate electrode to be fully attached to the patient to complete the path for the current to flow through and prevent cutaneous burns [17, 18].
