Consideraciones sobre Almacenes y Manejo de Inventarios

CT imaging plays an important role in lung cancer diagnosis, treatment, and follow-up.Current recommendations for imaging follow-up after SABR are generally based on retrospective evidence and expert opinion, rather than randomized data. Such follow-up serves 3 major goals: detection of local recurrence, detection of regional recurrence that may be amenable to salvage, and detection of new primary lung tumours, which occur at a rate of 2-10% per person-year [51, 59]. Based on the results of the National Lung Screening Trial [60], the American Association for Thoracic Surgery guidelines recommends 4 years of CT follow-up for patients who have undergone treatment for lung cancer and are eligible for additional treatment [61].

1.6.1.1

Radiation-Induced Lung Injury

Following radiotherapy to the lungs, the development of radiographic radiation- induced lung injury (RILI) on CT imaging can occur. Radiation delivered to the tumour

and surrounding lung parenchyma results in radiologic lung injury (pneumonitis and fibrosis) appearing as increased density on CT. The amount of radiation damage to normal tissue varies according to delivered dose, fractionation, dose rate, irradiated volume, and beam arrangement [62]. The appearance and patterns of RILI can also vary across follow-up time intervals. Radiation pneumonitis is typically seen in the acute setting within 6 months of treatment, following which it is classified as fibrosis [63]. From histopathological studies obtained after resection for false-positive imaging studies, these areas of lung injury are made up of a benign mixture of inflammatory cells,

fibrocytes and other benign features [64]. Lung injury following traditional 3D-

conformal radiation therapy (CRT) is often characterized by straight edges that conform

to treatment portals [65], as shown in Figure 1-1.

Figure 1-1: Radiation induced lung injury following a traditional anterior/posterior parallel opposed pair (treatment plan shown in (a)); (b) The resulting benign injury conforms to the treatment portals and is easily distinguished by a straight line.

(b) (a)

1.6.1.2

Common Appearances after SABR

Following SABR, benign RILI is nearly always present on follow-up CT imaging. Ablative doses of radiation result in radiographic changes appearing as an increased density and opacity on CT in the area of the high-dose region [66, 67]. Such CT changes

correlate closely with local delivered dose [68]. The total dose, fractionation, treatment

delivery technology, and tumour size are all factors which may affect the degree of radiographic lung injury [68, 69]. Such findings are not unique to lung SABR; they have also been described in other organs treated with stereotactic radiotherapy including brain and liver [70, 71].

The appearance of fibrosis is very common, occurring in 62% of patients within 6 months of treatment (acute) and 91% thereafter (late), as classified by a common

classification scheme (Figure 1-2) [66, 67]. This scheme classifies acute radiation

pneumonitis into consolidative or ground-glass opacity changes, which can further be

subdivided into diffuse (> 5cm) or patchy (≤ 5cm). Late radiation fibrosis can be categorized into modified conventional, mass-like, or scar-like patterns [66, 72]. A

modified conventional pattern has been described, defining a fibrosis pattern that is larger than the original tumour size, may be associated with ground-glass opacity, and may include consolidation, volume loss, and bronchiectasis that is similar to or less extensive than conventional radiation fibrosis [66, 73]. These radiographic changes can persist and continue to evolve even after 2 years following treatment.

Figure 1-2: Classification of post-SABR radiological changes.Adapted from Dahele et al. [66]

Morphologic patterns of fibrosis can also vary with treatment type; patients who underwent arc-based SABR had a predicted probability of a modified conventional pattern of 96.3% versus 68.9% for those who underwent fixed-beam treatment [69]. Although such radiologic lung injury occurs in nearly all patients by 2-years [66], only a small minority of patients develop clinical symptoms.

Several studies have examined simple dose-response relationships of HU changes following SABR. Increasing densities on CT post-SABR are seen with larger planning target volumes and longer time post-SABR, and these are most evident in regions receiving doses greater than 20 Gy [68]. Density changes post-SABR have also been shown to linearly increase to doses of 35-40 Gy and then plateau thereafter [68, 74]. The spatial location of fibrosis following SABR is on average 2.6 cm from the GTV position,

Diffuse Consolidation (>5cm) Patchy Consolidation (≤5cm) Diffuse GGO (>5cm) Patchy GGO (≤5cm)

Scar-like Mass-like Modified Conventional

Acute: ≤ 6 months

1.6.1.2.1

Radiation-Induced Lung Injury versus Recurrence

As a direct result of the highly ablative and conformal doses delivered with SABR, these benign radiographic changes can appear similar to a recurring tumour (Figure 1-3). Against the background of asymptomatic radiation-induced lung injury, accurate assessment of local recurrence is of paramount importance. These changes on CT can result in a major clinical dilemma with respect to accurately distinguishing patients with local recurrence from benign RILI, especially in cases with mass-like changes [76]. Although the classification scheme previously described is used to

categorize radiological changes following SABR, it is not used to distinguish recurrence from fibrosis.

Figure 1-3:Planning CT image for SABR treatment and subsequent follow-up imaging after radical treatment for early-stage primary lung cancer.

Distinguishing a recurrent tumour from fibrotic lung changes on CT can be

challenging for several reasons, as demonstrated in Figure 1-4. Both radiation-induced

lung injury and recurrent disease follow a similar temporal course, with lung fibrosis continuing to evolve two years after treatment, during which time, the majority of local recurrences occur [51, 66]. In contrast to lung injury following traditional 3D-CRT,

1-1), the pattern of lung injury on CT following SABR can be mass-like, due to the conformal nature of SABR [66, 76, 77]. Fibrosis may even appear on CT as an enlarging density and therefore can the mimic the growth of a local recurrence [77].

Misclassification of a recurrence as “benign fibrosis” can result in a missed

window of opportunity for curative-intent salvage treatment. Conversely,

misclassification of fibrosis as a recurrence may lead to unnecessary interventions, such as biopsy, imaging, chemotherapy, and even surgery, exposing patients to unnecessary risks and morbidity [64, 77-80]. The ability to accurately assess response is particularly important in light of the changing practice patterns for early stage NSCLC. As a growing number of patients are being treated by SABR [81], this clinical scenario will become more common. The treatment of a fitter patient population may result in a larger

proportion of patients who are candidates for salvage treatment in the case of recurrence. Finally, since recent data on potentially operable SABR patients suggest that failure may be higher than in the inoperable SABR cohort (with two-year lobar failure rates in one recent multicenter study [defined as recurrence anywhere in the irradiated lobe] as high as 19.2% [48]), accurate distinction between recurrence and fibrosis to permit early salvage is pressing clinical problem.

Figure 1-4:Radiological changes following SABR for an 85-year-old gentleman with biopsy proven adenocarcinoma. This patient received 54 Gy in 3 fractions with the treatment plan shown in (a). Radiological changes are seen (b) where 0m indicates the pre-treatment lesion measuring 2.0 cm. At 3 months post-SABR, there is presence of an enlarged ground-glass and semi-solid opacity measuring 4.3 cm. At 6 months there is interval reduction in size and a decrease in ground-glass opacity, with ongoing reduction in size at 18 months and 3 years post-treatment.

Several groups have reported patients with suspicious findings on CT and/or FDG-PET imaging who underwent salvage lung resection to have pathology show no

(a) (b) 0m +3m +6m +18m +3y Absolute 60 Gy 56.7 Gy 54 Gy 52.9 Gy 51.3 Gy 48.6 Gy 43.2 Gy 27 Gy 20 Gy 10 Gy

mass on CT follow-up for a patient treated with SABR (as shown in Figure 1-5) [77]. This was suspicious for recurrence and the patient underwent surgical resection, which demonstrated only a benign fibrotic scar. In most cases, persistent CT findings do not indicate recurrence: a recent study determining the fate of residual masses after SABR found that in 50 patients with masses present greater than 1 year following treatment, only 8 developed local recurrence [83].

Figure 1-5: (a) Pre-treatment CT image of a 79 year old gentlemen treated with stereotactic radiotherapy and (b-d) post-treatment follow-up CT images at 3, 6, and 9 months respectively. Enlargement of the nodule at 6 and 9 months raised suspicion of local recurrence and the patient was sent for surgical resection. (e) A 7 mm diameter tumour-like fibrous scar was observed on pathology, with sharply defined regions of fibrosis surrounding the scar and mild pleural thickening. Adapted from Takeda et al. [77]