Hu Xiao,Chen Ming

Thoracic radiotherapy has been demonstrated in a number of clinical studies that can reduce the local recurrence rate and improve the long-term survival rate in limited-stage small cell lung cancer (SCLC) patients and thus is an indispensable part in the comprehensive treatment of SCLC^{[1, 2]}. However,many controversies have existed for a long time in the implementation of thoracic radiotherapy (TRT),the target volumes for radiation is one of them^[3].

The current NCCN guidelines and the American College of Chest Physicians guidelines for SCLC recommend that patients with limited-stage SCLC receive TRT as early as possible or even deliver TRT currently with the first or second cycle of chemotherapy^[4]. But in general,SCLC patients at diagnosis often have huge tumor burden,TRT administered with cycle 1 concurrent chemotherapy would irradiate to relatively more normal lung volume. Moreover,it is usually difficult to differentiate obstructive atelectasis or pneumonia from cancer,and this will adversely affect the accurate delineation of target volumes of the primary disease. On the other hand,induction chemotherapy is still widely used in China. Patients received several cycles of induction chemotherapy are often encountered in daily clinical work. So,two main questions with regard to the design of irradiation volume for limited-stage SCLC after induction chemotherapy are prominent,namely,should we treat with the pre-chemotherapy or the post-chemotherapy tumor volume? Is elective nodal irradiation (ENI) necessary?

Up until now,there is only 1 prospective randomized study specially designed to solve these questions in limited-stage SCLC patients^[5]. This phase Ⅲ trial,performed by the Southwest Oncology Group,included 494 patients. After 4 cycles of induction chemotherapy,191 patients who achieved partial response or stable disease were randomized to radiation field based on either post-induction or pre-induction chemotherapy tumor volumes. The corresponding recurrence rates were similar in both arms: 32% for pre-chemotherapy volumes and 28% for post-chemotherapy volumes,respectively. The difference of median survival time were not statistically significant (51 weeks vs. 46 weeks,P＜0.05). However,life threatening and lethal toxicities were more common in the wide-volume radiotherapy arm than in the reduced-volume radiotherapy arm (17 of 93 patients vs. 8 of 98 patients) .

In the present point of view,although there are many deficiencies in the study carried out 30 years ago,for example,radiotherapy was designed by conventional X-ray simulation and patients received non-platinum chemotherapy regimens,the prospective study confirmed for the first time that irradiation to post-chemotherapy tumor extent did not significantly increase tumor recurrence,nor had significant adverse effect on overall survival,but reduced the radiotherapy toxicities. Thus post-chemotherapy volumes were regarded reasonable for target delineation. In a phase Ⅲ randomized controlled trial conducted by Bonner et al^[6] that compared the impact of two different dose-fraction schedules on local/regional disease progression free survival and overall survival,262 patients with limited-stage SCLC received etoposide and cisplatin (EP) regimen chemotherapy for 3 cycles,those who did not develop progressive disease were randomized to receive 1.8 Gy×28 daily fractions or 1.5 Gy administered twice a day for 32 fractions. The radiotherapy plans were designed with X-ray simulation. A planning target volume included post-chemotherapy gross tumor volume within a 2 cm margin,bilateral superior clavicular fossa,mediastinal and ipsilateral hilum as well. 90 cases developed local/regional recurrence,among them,7 were out of the radiation field and 5 of them were 2 cm away from the edge of radiation field,the rest 2 were within the 2 cm margin of radiation field edge. 2 of these patients failed within the pre-chemotherapy tumor volume. But this trial was not designed prospectively to study radiation target volume and it was not clear whether it was the primary tumor or mediastinal lymph nodes that developed out of field recurrence. While in other contemporary retrospective studies with compared "large field" or "reduced field" irradiation,the conclusions are inconsistent,or even contradictory to each other^{[7, 8, 9, 10]}.

In a prospective study reported recently by Hu et al^[11],three-dimensional conformal radiotherapy (3D-CRT) was applied. Patients with limited-stage SCLC received EP regimen chemotherapy for 2 cycles and then were randomized to receive TRT to either post or pre-chemotherapy tumor volume while elective nodal irradiation (ENI) was omitted in this study. In interim analysis,42 and 43 patients were randomized into these 2 arms respectively. The local failure rates were 31.6% and 28.6% (P＞0.05) respectively,no outfield failure was observed in both arms. The interim analysis results support irradiation to post-chemotherapy residual disease only,but the sample size of the study has not yet reached the designed requirements,the final conclusion needs to be obtained after the further accumulation of cases.CT-simulation based 3D-CRT can directly display the relationship between radiation dose and volume of the important organs. In our clinical practice,we require mean lung dose,V₂₀,V₃₀,V₄₀ and V₅₀ should be ≤16.77 Gy,V₂₀≤34.15%,V₃₀≤23.62%. If these parameters could not be meted,we usually prescribe 30 Gy to PTV then reduce the radiation field to GTV and boost to 45 Gy. 2 Clinical trials on elective nodal irradiation or involved field irradiation for mediastinal lymph nodes

As for the irradiation of lymph node regions,traditional radiotherapy target volumes included ipsilateral hilum,bilateral mediastinum and bilateral supraclavicular fossa,in accordance with the possible tumor spread sites. In the two-dimensional(2D) radiotherapy era,the application of ENI avoided missing of target volumes of the mediastinal and supraclavicular fossa lymph nodes and had a certain positive significance to ensure the quality of treatment. However,large radiation fields would reduce tolerance of patients to treatment,increase toxicity,affect radiation dose escalation,and even affect the completion of treatment. So,some scholars would irradiate high-risk lymph node regions (selective nodal irradiation). They believed with CT-simulation,target volumes can be intuitively contoured,makes omission of target volumes rare. Therefore,involved field radiotherapy (IFRT) can be used to include only visible tumor volumes on CT/MRI/PET and a small subclinical region that positive is nodal involved in,to deliver enough radiation doses to the highest density region of tumor cells,while the subclinical lesions could be eradicated by chemotherapy.

However,at present there are few large scale prospective clinical studies or meta-analysis results supporting the use of IFRT and in clinical practice,and so IFRT is not routinely applied. Kong et al^[12] completed a survey of 800 radiation oncologists,which reveals 31%,51% and 18% of the respondents chose extensive,selective or IFRT for SCLC respectively. Those against the use of IFRT are mainly for fear that it would lead to increased outfield regional recurrence of lymph nodes. In a phase Ⅱ clinical study conducted by Baas et al^[13],the second and third cycles of chemotherapy were administered with 3D-CRT,the 5 year survival rate of 37 limited-stage SCLC patients was 27%,all the 6 recurrences were exclusively developed within the radiation field. Belderbos et al^[14] updated Bass's data and found that of the 36 patients eligible for analysis,only 2 patients developed isolated outfield recurrence,1 patient was in the ipsilateral supraclavicular fossa,the other in contralateral hilum. 9 cases developed in-field failure,among them 4 cases were isolated in-field failure.

While DeRuysscher et al^[15] conducted a phase Ⅱ study based on CT-simulated radiotherapy reporting isolated nodal relapse rates after IFRT in 27 patients with limited-stage SCLC. A crude isolated outfield nodal failure rate of 11% (3 cases) was reported. All failure sites were in the ipsilateral supraclavicular fossa. Apart from that,2 cases developed isolated in-field failure,another 2 cases developed simultaneous in-field recurrence and distant metastasis. The outfield recurrence rate was higher than the authors' expectation. But due to the small sample size in the study,no definitive conclusions could be drawn.

In a retrospective analysis of 108 patients with limited-stage SCLC from 2 prospective phaseⅡ trials based on CT-simulation,IFRT was applied with concurrent chemotherapy. With a median follow-up time of 21 months,28 cases developed local/regional recurrences and 16 cases of them were within the radiation field,10 cases were outfield,2 developed both in and outfield failure. Isolated nodal failure of the ipsilateral supraclavicular was observed in 5 cases (4.6%),while supraclavicular nodal failure combined with metastasis was observed in 4 cases^[16].

Colaco et al^[17] reported on data from a randomized phase Ⅱ trial that 38 limited-stage SCLC patients received concurrent chemo-radiotherapy and IFRT. At median follow-up 16.9 months,31 patients were evaluable and 14 patients developed recurrence. 2 patients failed within planning target volume (PTV),4 patients within PTV and distantly and 2 patients with nodal recurrence outside PTV plus distant metastasis.

The aforementioned prospective study reported by Hu et al^[11] also used IFRT,the interim analysis showed that the overall failure rate was 30% (24 of 80 patients),the isolated outfield recurrence rate was 2.5% (2 of 80 patients),simultaneous outfield and distant metastasis rate 3.8% (3 of 80 patients),out-of combined with in-field failure was not observed. All outfield field failure was exclusively developed in the ipsilateral supraclavicular fossa. 3 Possible approaches to overcome supraclavicular fossa nodal failure

The aforementioned trials were all based on CT-simulated radiotherapy and applied IFRT,it is remarkable that although outfield failure of mediastinal lymph node was not observed,the outfield recurrences were almost all developed in the supraclavicular areas.

The reason may lie in that the complicated anatomy of supraclavicular fossa would result in omission of tiny metastatic lymph nodes. What is more,the artifacts caused by contrast agent through the subclavian vein and bones of shoulder joint might also affect the judgment of the supraclavicular lymph nodes.

In short,adequate attention should be paid to supraclavicular areas when delineating radiotherapy target volumes for limited-stage SCLC.

Hu et al^[11] further studied the risk factors for outfield failure of supraclavicular lymph nodes by regression analysis. The results showed that mediastinal N₃ disease was the only factor that was found to predict outfield recurrence (P＜0.05,odds ratio= 29.33; 95% CI: 2.94 to 292.38). In a prospective study including 117 lung cancer patients comparing the value of palpation,ultrasonography (US),and CT in diagnosing metastasis of supraclavicular lymph nodes,van Overhagen et al^[18]performed US guided fine-needle aspiration cytological analysis in patients with supraclavicular nodes with a short-axis diameter of 5 mm or greater. Cytological diagnosis was used as the reference standard. The authors reported that CT (P<0.05) and US (P<0.05) were significantly more sensitive than palpation for detecting supraclavicular metastasis,but there was no significant difference between CT and US (P>0.05). Therefore,we recommend ultrasonography of the supraclavicular before target delineation.

The emergence of PET/CT has put tumor diagnosis a step forward. Studies showed that in patients with SCLC,PET/CT examination can detect 5%-12.5% of supraclavicular lymph node metastasis rate when it was negative on contrast enhanced CT scans^{[19, 20, 21, 22]}.

Feng et al^[23] retrospectively analyzed 239 patients with limited-stage SCLC,clinical characteristics and mediastinal lymph node metastasis were analyzed for association with supraclavicular lymph node metastasis. The results showed that the overall supraclavicular lymph node metastasis rate was 34.7%. Multivariate analysis showed that only the mediastinal level Ⅱ (OR=16.10, P<0.05) and level Ⅲ (OR=5.60,P<0.05) lymph node metastases were significantly associated with supraclavicular lymph node metastasis. If prophylactic irradiation therapy is considered,the nodal clinical target volume of irradiation should include bilateral lower para-recurrent laryngeal neural region (level Ⅰ) and the para-internal jugular venous region (level Ⅲ). 4 Impact of PET/CT on the design of radiotherapy target volumes

Studies have reported that 16%-38% of patients changed radiation target volumes after PET/CT examination,especially the obvious change of mediastinal lymph nodes in the target volume.

van Loon et al^[24]reported 21 patients with limited-stage SCLC,for each patient,two 3D-CRT plans were made with selective irradiation of involved lymph nodes based on CT and PET. PET changed radiation field in 5 patients. In 3 patients,this was due to a decrease,and in 2 patients to an increase in the number of involved nodal regions. Based on the results,van Loon et al^[22] carried out a phase Ⅱ study of 60 patients with limited-stage SCLC. Only the mediastinal lymph nodes and primary tumor involved on pretreatment PET scan were irradiated. Compared with CT scans,PET/CT resulted in a difference in involved nodal stations in 30% of patients,among them,PET/CT detected supraclavicular lymph node metastasis in 3 patients,while negative on CT scans. Of 60 cases,2 experienced isolated regional failure,while these failure sites were negative on both pretreatment CT and PET/CT scans. Recently,Shirvani et al^[25]reviewed 60 patients with limited-stage SCLC who were staged with PET/CT before treatment and were treated with involved-field intensity-modulated radiotherapy,only 1 patient developed isolated out field failure. In and outfield recurrence was observed in 1 patient,outfield failure combined with distant metastasis was developed in 2 patients. The outfield recurrence sites were para-trachea in 1 patient and supraclavicular fossa in 2 patients.

Based on these studies,the investigators believe that it is safe and feasible to delineate mediastinal lymph node target volumes and deliver IFRT by referring to PET/CT examination,and it is conducive to the radiotherapy dose escalation and may avoid unnecessary damage to normal tissues as well. 5 Conclusions

Up till now,high level prospective studies on the radiotherapy target definition of limited-stage SCLC are still lack. Based on existing studies,it is appropriate to include only residual primary tumor after chemotherapy into radiation target volumes,the primary tumor recurrences were almost located within radiation field. The mediastinal lymph node irradiation is more and more inclined to use CT-simulation based IFRT,because isolated nodal failures are rare. But the whole lymph node regions where positive lymph nodes belong to should be included in radiation target volumes,even if the lymph nodes achieved complete remission after chemotherapy.