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Commentary |
Lung Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK
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Introduction |
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 Top Introduction ConclusionsReferences |
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Role for early diagnosis and advances in staging of NSCLC
Dr Tim Eisen of the Royal Marsden Hospital presented data on screening and genetic predisposition to NSCLC. The early lung cancer action project (ELCAP) was designed to evaluate baseline and annual repeat screening by low radiation dose computed tomography (LD-CT) in 1000 high risk individuals (defined by age >60 years, and >10 pack year history of cigarette smoking). Baseline chest radiograph and LD-CT findings were reported [1]. 3% of individuals were biopsied for suspicious lesions. Of these, 96% had lung malignancy and 93% were resectable. Only 26% of individuals with malignant disease diagnosed on LD-CT had abnormal chest radiographs. Further results and implications of LD-CT awaited, in particular the effects of screening on survival.
Methods for determining individuals at high risk of developing NSCLC continue to be evaluated, aimed at targeted screening in NSCLC. Currently these include cytological immunostaining, identification of genetic polymorphisms that predispose to NSCLC as well as sensitivity to known environmental carcinogens. The genetic lung cancer predisposition study (GELCAPS) aims to establish a collection of DNA samples and epidemiological data from 3000 patients with lung cancer and a group of controls for future study.
Advances in radiological and clinical staging of NSCLC
Accurate staging and patient selection is critical when considering patients for radical treatment and for comparing outcomes in international clinical trials.
Dr Sheila Rankin from St Thomas' Hospital reported that CT remained the optimal imaging modality for T1 and T2 NSCLC. T3 tumours with possible chest wall or mediastinal invasion remain very difficult to assess by CT which could not reliably predict invasion (sensitivity for CT is as low as 40%). CT may overestimate the degree of invasion and suggest lesions were inoperable, thereby potentially denying the patient radical treatment. In such cases, the superior soft tissue contrast of MRI compared with CT may be better at differentiating chest wall invasion as well as assessing superior sulcus tumours.
Cross-sectional imaging of the mediastinum with CT or MRI is a standard method used to determine the presence of lymph node metastases. Nodes that have a short axis diameter greater than 1 cm are typically considered abnormal and likely to harbour metastases. Functional imaging using 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) is dependant not on nodal size but metabolic activity is more accurate for staging nodes. False positive rate for FDG-PET however is 15%, so at present the technique is neither sensitive nor specific enough to obviate the need for cervical mediastinoscopy.
Dr Pallav Shah of the Royal Brompton Hospital presented data on techniques to sample difficult to access mediastinal and hilar nodes for pathological staging without formal mediastinoscopy. These include transbronchial fine needle aspiration (FNA), endoscopic ultrasound guided FNA, endobronchial ultrasound-guided FNA and transthoracic FNA.
Defining the role of chemotherapy in the treatment of NSCLC
Dr Angela Davies of The UC Davis Cancer Centre, California presented the South West Oncology Group (SWOG) experience with chemoradiation for NSCLC.
Concomitant chemoradiation is the standard of care in the USA for inoperable Stage III NSCLC based on the results of the RTOG 9410 Trial presented at ASCO 2003. This three arm study compared two cycles of neo-adjuvant cisplatin and vinblastine followed by radiotherapy 60 Gy/30 F/6 weeks versus concomitant chemoradiation with two cycles of cisplatin and vinblastine and radiotherapy 60 Gy/30 F/6 weeks versus concomitant chemoradiation with two cycles of cisplatin and oral etoposide and hyperfractionated radiotherapy delivering 69.6 Gy in 1.2 Gy twice daily fractions over 6 weeks. Median survival was improved by 3 months in favour of concomitant chemoradiation. Grade 3–4 non-haematological toxicity with hyperfractionated radiotherapy was in excess of 60% with no significant improvement in median survival compared with conventional treatment. In the UK, this trial has not been influential in changing practice to date, and a trial comparing sequential and concomitant chemoradiation using an accelerated radiotherapy schedule of 55 Gy/20 F/4 weeks is soon to commence (SOCCAR).
There is currently a resurgence in interest in adjuvant/consolidation chemotherapy in NSCLC. SWOG have evaluated consolidation chemotherapy following chemoradiation in two Phase II trials. In SWOG 9019 [2], 50 patients received concomitant chemoradiation followed by 2 cycles of cisplatin and etoposide. In SWOG 9504 [3], 83 patients received concomitant chemoradiation followed by 2 cycles of docetaxel. Better results were reported with docetaxel resulting in 3 year overall survival of 37% and median survival of 26 months. Unfortunately this was a single arm study and so it is uncertain whether the impressive results are a real improvement, or due to patient selection or good luck. Despite this, the latter regimen has been adopted as the standard treatment arm in a current Phase III Intergroup Trial of maintenance treatment with ZD1839 (gefitinib) versus placebo.
The Hoosier Oncology Group is currently undertaking a Phase III trial of concomitant chemoradiation with cisplatin and etoposide with or without two cycles of docetaxel consolidation which hopefully will answer the above question.
Defining a role for concomitant chemoradiotherapy for locally advanced inoperable NSCLC in the UK
Dr Matthew Hatton from Weston Park Hospital, Sheffield reported that in the UK the current standard radical treatment for inoperable, localized NSCLC is continuous hyperfractionated accelerated radiotherapy (CHART). CHART has been difficult to implement in many centres due to lack of resources. A Phase II study of CHARTWEL (week end less) delivering a higher total dose of 60 Gy in 1.5 Gy three daily fractions over 18 days resulted in 2 year survival of 47%. This has led to a current German Phase III trial comparing this with conventional radiotherapy.
Professor Kostas Syrigos from Sotiria General Hospital, University of Athens reported on the Eastern Co-operative Oncology Group (ECOG) study 2597 [5], which evaluated neoadjuvant chemotherapy with carboplatin and paclitaxel for two cycles followed by radiotherapy. Patients in the trial were randomized to radiotherapy given conventionally 64 Gy/32 F/6
weeks or as hyperfractionated accelerated radiotherapy (HART) total dose 57.6 Gy in 1.5 Gy three daily fractions over 15 days excluding treatment at weekends. There was a 13% 3-year survival advantage for neoadjuvant chemotherapy followed by HART with a median survival of 21 months versus 12 months. The UK has responded to these results with the launch of the INCH Trial: induction chemotherapy and CHART in NSCLC. The objective of this study is to compare 3 cycles of induction chemotherapy with cisplatin and vinorelbine followed by CHART versus CHART alone in inoperable NSCLC. Dr Dennis Yiannakis from Derriford Hospital, Plymouth reported that the chemotherapy regimen chosen is based on the CALGB 9431 study which compared cisplatin and gemcitabine versus cisplatin and paclitaxel versus cisplatin and vinorelbine as induction chemotherapy, which showed overall equivalent results but a better toxicity profile with the cisplatin and vinorelbine combination.
Radiation dose escalation – the NKI experience
Dr Jose Belderbos from the Netherlands Cancer Institute discussed the role of radiotherapy dose escalation. Early Phase III trials conducted by RTOG 73-01 and 83-01 confirmed improved local control with radiotherapy doses up to 70 Gy/35 F/7 weeks using conventional radiotherapy techniques. Dr John Armstrong from St Luke's Hospital, Dublin reported that recent advances in target delineation using image co-registration with FDG-PET–CT, control of organ motion, respiration-correlated imaging and improved treatment execution may allow further dose escalation and better local control rates. Dr Belderbos reported that the NKI-AVL Phase I/II dose escalation trial was commenced in October 1998. It included Stage I–IIIb medically inoperable NSCLC patients with good performance status and respiratory function. Maximum tolerable radiation doses and dose limiting toxicities were determined based on dose computation algorithms and alpha/beta ratios. Risk groups were defined based on estimated risk of developing radiation pneumonitis. Five risk groups were assigned for each TNM stage (Table 1
). Target volume included primary tumour and enlarged, metabolically active nodes as determined by CT and FDG-PET data. Fraction sizes delivered were 2.25 Gy and treatment time did not exceed 6 weeks.
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Information from the dose escalation study has lead to the development of a multicentre Phase III HiCoRT Trial (High versus Conventional dose Radiotherapy), CKTO 2003-06. This trial will recruit patients with inoperable T1–2, N0 M0 NSCLC randomized to conventional radiotherapy delivering 67.5 Gy/30 F/6 weeks versus high dose radiotherapy 87.75 Gy/39 F/6 weeks. This dose increase should result in a 15% increase in local control. The primary endpoint of the study is freedom from local recurrence at 2 years. Secondary endpoints include quality of life and overall survival. This study is open to centres outside The Netherlands.
Strategies to control target motion during radiotherapy were discussed by Dr Ethan Lyn of Mount Vernon Hospital. One of the challenges in NSCLC irradiation is overcoming tumour motion due to respiratory movement. At present, margins of 1–1.5 cm are added to the clinical target volume to account for this. Methods of minimizing error and possibly permitting smaller margins are currently under evaluation.
Tumour immobilization by voluntary methods such as deep inspiration breath hold do not require any special apparatus. However the results are not accurately reproducible and the technique is tiring for patients during a full course of radiotherapy treatment. Image-guided radiotherapy techniques rely on a surrogate marker for the tumour coupled with an imaging technique to detect its position. This allows tracking of the tumour during free breathing with apparatus coupled to the patient and the linear accelerator treatment beam. This can be done with reflectors placed on the skin which are illuminated by infrared emitting diodes tracked by an infrared sensitive camera. An alternative technique involves the implantation of internal markers at the site of the tumour that can be tracked fluoroscopically. Tumour position varies in all directions during respiration and the complexity of this type of treatment delivery can in itself be subject to further errors.
Gating in breath-hold using a spirometric active breathing control device eliminates the error due to respiratory excursion and improves the accuracy of treatment delivery. It has been demonstrated that radiotherapy treatment with the breath held in moderate deep inspiration reliably reduces the volume of normal lung irradiated and may allow dose escalation to the target.
Does intensity-modulated radiotherapy have a role in the radical treatment of NSCLC?
Dr Michael Brada of the Royal Marsden Hospital reported on progress with intensity-modulated radiotherapy. For NSCLC a treatment technique using five fields has been shown to improve the volume of lung in the target volume receiving 90% of the prescribed dose and reduces the volume of normal lung receiving 20 Gy when compared with conformally planned 3-field radiotherapy. Increasing the dose differential between the target and critical structures can potentially allow dose escalation to the tumour while sparing radiation dose to the remaining normal lung, oesophagus, heart and spinal cord. In order to implement radiotherapy using techniques that allow dose escalation to the target it is important that set-up and target motion are accounted for and minimized and that target delineation is accurate and reproducible.
Could there be a role for anti-EGFR therapies in conjunction with radical radiotherapy?
Dr Susanne Rogers of the Institute of Cancer Research reported that epidermal growth factor receptor (EGFR) is over-expressed in NSCLC and results in a more aggressive clinical course as it plays a role in proliferation, invasion, angiogenesis, development of metastases and is antiapoptotic. Radiotherapy appears to trigger EGFR expression resulting in accelerated repopulation. EGFR inhibition can be induced by monoclonal antibodies to EGFR such as cetuximab, small molecule tyrosine kinase inhibitors such as gefitinib and anti-EGF vaccines currently undergoing Phase I trials. Clinical experience to date with gefitinib has shown excellent tolerability and bioavailability [6] (Table 2).
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Conclusions |
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Received for publication March 25, 2004. Revision received June 28, 2004. Accepted for publication July 28, 2004.
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