Radiotherapy as treatment option in biliary cancer patients: a national survey of AIRO (Italian Association of Radiation Oncology) Gastroenterology Group.

BACKGROUND: The aim is to find out how many radiation oncology centres treat biliary duct carcinoma (BDC), what treatments they offer and whether they would be interested in developing prospective trials.
MATERIALS AND METHODS: A questionnaire was posted to all 220 Italian Radiation Oncology Centres. The survey consisted of 31 eligibility questions in a combination of multiple and forced choice formats addressing the following parameters: characteristics of the centre, numbers of BDC patients treated, treatment options, radiotherapy parameters (target definition, schedule, technique, dose constraints) and interest in developing future randomized trials.
RESULTS: No major differences emerged in BDC management, whatever the site, and whether it was resectable or not. Discrepancies in routine clinical practice were, however, observed with lack of agreement on expansion margins, dose constraints and treatment schedules for the stereotactic technique and palliative treatments.
CONCLUSIONS: The present survey attempted to fill the gaps in the role of radiotherapy in patients with BDC. Since lack of prospective randomized studies and disease rarity have mitigated against an evidence-based approach, patients with BDC should be enrolled in prospective studies. The above-mentioned results should also emphasize the need to combine analysis of treatment results from all Italian centres in order to create predictive models.

Introduction

Biliary duct carcinoma (BDC) accounts for at least 3–4% of all gastrointestinal tumours; it is associated with poor prognosis as < 20% of patients are suitable candidates for surgery which is the only effective treatment [1, 2]. Prognosis depends in part on the anatomic location of the tumour, which affects its resectability. Total resection is higher for distal biliary duct lesions than for proximal ones. However the rate of relapse is as high as 60–75%, even if clear resection (R0 resection) is possible [3] In patients with locally advanced disease (mainly status N+ or R1–R2), postoperative external beam radiotherapy (EBRT) plus chemotherapy may improve local control and overall survival [4-6]. In unresectable disease, EBRT (plus intra-luminal brachytherapy (BRT) in the extrahepatic cholangiocarcinoma) with or without chemotherapy may affect clinical outcomes [7, 8]. In the palliative setting, the addition of BRT to the biliary stent position reduces the tumour growth and prolongs biliary patency. The safe and effective combination of biliary stent and BRT may improve quality of life [9-11].

Recently, preliminary studies related to stereotactic body radiotherapy in both intrahepatic and extrahepatic disease have documented an acceptable toxicity profile and local control with a dose-response relationship [12, 13].

Despite these data, the role of radiotherapy in biliary carcinoma remains under debate. Little or no scientific evidence is available in favour of one approach or another because prospective randomized trials are lacking due to disease rarity. Recommendations from national [14, 15] and international guide-lines [16, 17] are mainly based on retrospective studies, systematic reviews or, more often, indications for radiotherapy are discussed in multi-disciplinary groups, with choice of treatment at the physicians’ discretion [14, 18, 19].

Within the Italian Association of Radiation Oncology, the Gastroenterology Group conducted a nationwide questionnaire-based survey on BDC, with the aims of finding out how many radiation oncology centres treat BDC, what treatments they offer and whether they would be interested in developing future randomized trials.

Materials and methods

In June 2015, a questionnaire was posted to all 220 Italian Radiation Oncology Centres. Practising radiation oncologists were asked to fill it in and return it by post, fax or email before December 2015. No fee or incentive was offered; participation was voluntary and anonymous. To encourage participation, AIRO co-ordinated two follow-up e-mails to all participants within 1 month of the initial e-mailing. The survey consisted of 31 eligibility questions in a combination of multiple and forced choice formats addressing the following parameters: characteristics of the centre (questions 1–6), numbers of BDC patients seen, treated, followed-up with radiation therapy per year (questions 7–10), therapy for the intra-hepatic and extra-hepatic biliary tracts and the gallbladder (questions 11–13), target definition and treatment schedule (questions 14–18), radiotherapy technique and dose constraints (questions 19 and 20), brachytherapy (questions 21–31) and interest in developing future randomized trials (32) (Fig. 1). For the statistical analysis data are shown as frequencies.

Figure 1

A questionnaire was posted to Italian Radiation Oncology Centres

Results

In total, 36/220 (16%) centres responded to the questionnaire. Responders were distributed similarly in northern and central Italy (15 (41.6%) and 19 (52.7%), respectively) but only 2 (5.7%) responded from the south of Italy. The number of patients with BDC who were treated per year ranged from < 5 patients in 23 (63.8%) centres, ≤ 10 patients in 4 (11.1%) and > 10 patients in 1 (2.7%). Intention to treat in 75% centres was both palliative and adjuvant/radical.

For resectable disease, adjuvant radiotherapy was recommended when margins and lymph-nodes were positive by 22 responders (61%) for intra-hepatic disease, by 28 centres (77.7%) for extra-hepatic disease, and by 25 centres (69.4%) for gallbladder disease. Chemotherapy in combination with radiotherapy was the most common choice (52.7% intra-hepatic disease, 63.8% extra-hepatic disease and 50% gallbladder). Figure 2 shows treatment modalities for each BDC subtype.

Figure 2

Choice of treatment modality by biliary duct carcinoma subtypes. RT — radiotherapy; CT — chemotherapy

For inoperable disease, exclusive radiotherapy was considered by 12 centres (33.3%) for intra-hepatic disease and by 14 centres (38.8%) for gallbladder disease. Chemotherapy alone was chosen by 9 centres (25%) for intra-hepatic disease and by 8 centres (22.2%) for gallbladder. Concomitant and sequential chemotherapy was recommended by 15 centres (41.6%) in intra-hepatic disease and by 14 centres (38.8%) for gallbladder. Six centres (16.6%) used concomitant chemotherapy for intra-hepatic disease and 5 centres (13.8%) for gallbladder.

For inoperable extra-hepatic disease, 17 centres (47.2%) considered only external beam radiotherapy (EBRT), 5 (13.8%) provided EBRT combined with BRT, 3 offered (8.3%) BRT alone and 2 (5.5%) did not prescribe radiotherapy.

Fluoropyrimidine (capecitabine, 5-fluorouracile), gemcitabine and cisplatin in monotherapy or in combination with each other were the most common chemotherapy agents for all disease sites, independently of disease stage.

Three dimensional conformal techniques (3DCRT), stereotactic radiotherapy, and intensity modulated radiotherapy (IMRT) were the most common EBRT techniques used whatever the site. Figure 3 illustrates distribution of radiotherapy techniques.

Figure 3

Radiotherapy technique. 3D-CRT — three dimensional conformal radiotherapy; SBRT — stereotactic radiotherapy; IMRT — intensity modulated radiotherapy; IGRT — image guided radiotherapy

Conventional fractionation was the most common schedule used (58.3% of centres for intra-hepatic, 75% of centres for extra-hepatic disease and 66.6% of centres for gallbladder). Figure 4 reports radiotherapy schedules. Both in the adjuvant setting and locally advanced unresectable disease, there was an agreement between the responding centres to the survey as a total dose of 50–54 Gy and 54–60Gy, respectively, was recommended (Fig. 5).

Figure 4

Schedule treatment. C —conventional; H — hypofractionated; SIB — simultaneous integrated boost

Figure 5

Total dose delivered in advanced disease.

There was no agreement on expansion, dose constraints and treatment schedules for stereotactic radiotherapy or palliative treatment.

Appropriate Italian national and international guidelines were followed by 21 centres (58.3%) for intra-hepatic disease, by 25 centres (69.4%) for extra-hepatic disease and by 24 centres (66.6%) for gallbladder. Figure 6 lists the most popular guidelines.

Figure 6

Use of Guidelines. IST — institutional; N — national; INT — international; CC — clinical context Intra-hepatic Extra-hepatic Gallbladder

Only 5 centres (13.8%) performed BRT; but all agreed on intention to treat, treatment planning, doses and stent use. Most centres (69.4%) were interested in developing future prospective randomized trials.

Discussion

To our knowledge, this is the first survey about radiation oncology approaches to BDC. As usual, caution needs to be exerted when interpreting results from any questionnaire because they provide an image of reality that sometimes does not coincide with clinical practise as a result of the personal behaviour of the radiation oncologist responding to the survey. Nevertheless, on the whole, no major differences emerged in BDC management, whatever the site, and whether it was resectable or not. Good agreement may be due to the Gastrointestinal Italian Guidelines [14] that supported decision-making even in the absence of randomized trials.

Discrepancies in routine clinical practice were, however, observed with lack of agreement on expansion margins, dose constraints and treatment schedules for the stereotactic technique and palliative treatments. Unfortunately, survey responses precluded drawing any conclusions about the underlying reasons for these differences but they do suggest that future clinical trials should focus on providing evidence for optimizing and standardising BDC treatment.

Only 16% of Italian Radiation Oncology Centres responded to the questionnaire; this attitude may be related to the low incidence of the disease and lack of interest. Given the rarity of BDC, referring patients to specialised centres should perhaps be considered. In fact, 27/36 responding centres (75%) treated fewer than 10 patients/year and only 3 (3.3%) included patients in investigational protocols. These data are similar to those reported by a pattern of practice study on radiotherapy for BDC carried out by the Japanese Society of Radiotherapy Oncology [20].

Most radiation oncologists recommended adjuvant treatment in the subgroups of patients with pathologically positive nodes and/or microscopic residual disease (R1) as two meta-analysis showed a significantly lower mortality rate of patients treated with adjuvant radiotherapy than those treated with surgery alone [4–6, 21]. Unfortunately, no ongoing prospective study is analyzing the role of radiotherapy and one of the few randomized studies has been closed for poor accrual [22].

In the unresectable disease, the attitude of radiation oncologist was highly dependent on the anatomic location of the tumour; as radiotherapy alone or in combination with chemotherapy was recommended in only one third of intra-hepatic and gallbladder disease cases but in about two third of extra-hepatic tumours. These data may be related to the absence of efficacy arising from published studies and, therefore, to the awareness of therapeutic failure, even if recently in patients with intra-hepatic non-surgical tumour, the addition of radiotherapy to chemotherapy has significantly improved the overall survival [8].

The survey reveals a good agreement of radiation oncologists related to the adjuvant and radical treatment and the doses delivered, on the other hand. a poor agreement is documented in the setting of stereotactic radiotherapy. In the few literature data, the feasibility and efficacy of this procedure is documented in terms of toxicity and local disease control. However, these studies were carried out on a limited number of cases, using different fractionations and total dose delivered; the probable dose-response correlation requires further investigation [12, 13, 23, 24].

First treatment schedule, whether for exclusive or adjuvant therapy, was, in 75% of Centres, a total dose of 50–54 Gy as delivered with EBRT. The same attitude was reported by the Japanese pattern of practice for BDC and guide-lines [20]. IMRT is the most used technique and this data is supported by the SWOG 8909 trial [25] which documents the feasibility and efficacy in terms of toxicity and outcomes in the adjuvant setting. Nevertheless, higher doses are limited by the tolerance of adjacent organs at risk, such as the liver, duodenum and stomach. In the unresectable extra-hepatic disease, BRT may overcome this limitation because it is associated with high radiation dose conformity within the target volume, rapid dose fall-off in adjacent organs at risk, relatively short treatment times and good functional outcomes. In patients with unresectable BDC, studies comparing EBRT plus BRT with EBRT alone showed better local control in the first group but no difference in the 2-year disease specific survival [9, 18, 19]. In patients with malignant biliary obstruction BRT played a major role in the palliative setting as stenting in combination with BRT provided a longer patency and survival [26-29]. Unfortunately, the present survey showed that only 5 Italian centres (13.8%) performed BRT, perhaps because of lack of experience and skill or current interest in modern EBRT equipment. However, the limited use of BRT was also documented in the Japanese pattern of practice [20].

Many centres recommended adjuvant chemotherapy in combination or not with radiotherapy. This attitude seems to be mainly based on two randomized trials and one meta-analysis [4, 30, 31] Recently, the results of two randomized phase III trials have been reported. The French trial (ACCORD 12-Prodige 18) comparing follow-up after surgery vs. adjuvant chemotherapy with gemcitabine-oxaliplatin did not show differences in terms of overall and disease-free survival [32]; while in the preliminary results of the BILCAP study adjuvant capecitabine obtained an improvement of clinical outcomes over postsurgical follow-up alone [33]. Not surprisingly, the most commonly used drugs for chemotherapy were fluoropyrimidine (capecitabine or 5-fluorouracil), gemcitabine and cisplatin in monotherapy or in combination. The phase III ABC-02 study showed that a combination of gemcitabine and cisplatin improved overall and progression-free survival by 30% over gemcitabine alone which may be considered the standard regimen in BDC [34]. Apart from the SWOG trial no prospective phase II or randomized trials using a combination of gemcitabine-capecitabine have been published.

The main limitation of the present investigation was the response rate to the survey. It appears low and is, indeed, lower than response rates elsewhere, [35] probably due to the rarity of BDC. Despite the fact that this survey provided a snapshot of attitudes towards BDC in Italian radiotherapy centres at that particular moment in time. It is to be hoped that these data will provide the basis for future clinical studies so as to ensure an evidence-based approach to BDC.

Conclusions

The present survey attempted to fill the gaps in the role of radiotherapy in patients with BDC. Since lack of prospective randomized studies and disease rarity have mitigated against an evidence-based approach, patients with BDC should be enrolled in prospective studies. We think the above-mentioned results should also emphasize the need to combine analysis of treatment results from all Italian centres in order to create predictive models [36].