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Current approaches for prophylactic cranial irradiation in extrapulmonary small cell carcinoma a

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Ozan Yazıcı , Nuriye Y. Ozdemir , Mehmet A.N. Sendur , Sercan Aksoy & Nurullah Zengin a

Ankara Numune Education and Research Hospital AnkaraTurkey

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Hacettepe University Cancer Institute AnkaraTurkey Published online: 26 May 2015.

Click for updates To cite this article: Ozan Yazıcı, Nuriye Y. Ozdemir, Mehmet A.N. Sendur, Sercan Aksoy & Nurullah Zengin (2014) Current approaches for prophylactic cranial irradiation in extrapulmonary small cell carcinoma, Current Medical Research and Opinion, 30:7, 1327-1336 To link to this article: http://dx.doi.org/10.1185/03007995.2014.904771

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Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2014.904771

Vol. 30, No. 7, 2014, 1327–1336

Article ST-0408.R1/904771 All rights reserved: reproduction in whole or part not permitted

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Review article Current approaches for prophylactic cranial irradiation in extrapulmonary small cell carcinoma

Ozan Yazıcı Nuriye Y. Ozdemir Mehmet A.N. Sendur Ankara Numune Education and Research Hospital, Ankara, Turkey

Sercan Aksoy

Abstract Background: Small cell lung cancer (SCLC) patients, who have achieved complete or partial response after chemotherapy, should be followed with prophylactic cranial irradiation (PCI). PCI for extrapulmonary small cell carcinoma (EPSCC) is not routinely recommended. The purpose of this review is to discuss all aspects of PCI in management of EPSCC.

Hacettepe University Cancer Institute, Ankara, Turkey

Nurullah Zengin Ankara Numune Education and Research Hospital, Ankara, Turkey Address for correspondence: Mehmet Ali Nahit Sendur MD, Ankara Numune Education and Research Hospital, Department of Medical Oncology, 06100, Sihhiye, Ankara, Turkey. Tel.: +90 312 508 4600; Fax: +90 312 508 4914; [email protected] Keywords: Extrapulmonary small cell carcinoma – Prophylactic cranial radiation – Radiotherapy – Small cell carcinoma Accepted: 12 March 2014; published online: 4 April 2014 Citation: Curr Med Res Opin 2014; 30:1327–36

Scope: The PubMed database and the database of online abstracts of the American Society of Oncology (ASCO), ASCO Genitourinary (GU) Cancers meetings and clinical trials were searched up to 15 October 2013 using the following search keywords: ‘SCC or EPSCC of each organ site and prophylactic cranial radiotherapy’. The language of screened abstracts and manuscripts was limited to English. The papers which included the largest case series and data of cases about prophylactic cranial radiotherapy and/or were published in the last 10 years were selected. Findings: Many single center studies showed low incidence of brain metastasis in patients with esophageal small cell carcinoma (SCC). Due to the low incidence of brain metastasis, PCI is not recommended for esophageal SCC. Genitourinary, colorectal, small bowel and appendix cranial metastatic SCCs are extremely rare. Therefore, PCI is not recommended. The frequency of brain metastasis of prostate small cell carcinoma is much higher (16–19%) compared to other counterparts of EPSCC. PCI can be performed in selected cases of prostate SCC. High rates (41%) of brain metastasis develop in head and neck SCC. PCI should be considered for patients with head neck SCC. Conclusion: In the literature, the brain metastasis incidence of EPSCC might vary from 1.7% up to 40%. In many patients with ESPCC, PCI is not recommended. However, we have to keep in mind that primary head and neck and prostate SCC are exceptions due to the high incidence of cranial metastasis; PCI should be recommended for these patients on an individual basis.

Introduction In the 1930s, EPSCC was defined as a different clinical entity from SCLC1. Incidence of EPSCC increases with age and reaches a peak in the seventh decade. EPSCC is a rare and aggressive disease, which represents up to 5% of all cases with SCLC2. The most common EPSCC is in the gastrointestinal tract, especially the esophagus and colon; following that is the genitourinary tract, particularly the bladder and uterine cervix, and the head and neck region, ! 2014 Informa UK Ltd www.cmrojournal.com

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particularly the larynx3–7. The clinical course, etiological factors, survival and frequency of brain metastases differ between SCLC and EPSCC. Although EPSCC is a different disease, there are many similarities between the two diseases. Many common features are shared by EPSCC and SCLC including: histological appearance, poor clinical outcome and short lasting remission after chemotherapy or radiotherapy8. Until now, there have not been any randomized studies reporting the treatment management of EPSCC. Because of the pathological similarities between SCLC and EPSCC, well established treatment protocols of SCLC guide the treatment of EPSCC. The 5 year overall survival (OS) rate of EPSCC is less than 15% but some patients have a more favorable OS9,10. As expected, locoregional disease has better OS compared to extensive disease. However, the prognosis depends on the organ where SCC originates. Many clinicians adopt information about treatment of EPSCC from studies of SCLC. Treatment management recommendations for EPSCC are obtained from single center experiences and studies about SCLC3,10,11. As a consequence of these, some aspects of EPSCC treatment are differentiated from treatment of SCLC, especially the concept of PCI. For patients with EPSCC, the issue of PCI is still controversial. In this review, we aim to discuss all aspects of PCI in the management of EPSCC. We defined the organs and systems except the lungs that might be involved with small cell carcinoma. For each organ site we entered the name of the organ or region and small cell carcinoma and/or PCI as search terms. Although there has been no randomized trial in this field, we included the largest case series, retrospective analyses and single center studies published in the last 10 years. However, for some organs or regions there have been no published series or retrospective studies in the last 10 years; in these cases we selected the papers including the largest cases without considering the publication date. The papers were selected by the authors according to aim of the review. Afterwards, we discuss the evidence about PCI for treatment of EPSCC for each organ site and whether to adopt the information about PCI for SCLC to EPSCC.

Methods Publication search A computerized search was performed of the PubMed database and the database of the online abstracts of ASCO meetings, ASCO-GU Cancers Symposium and ongoing studies on clinical trials using the following search keywords: ‘small cell carcinoma or EPSCC of; gastrointestinal, esophagus, stomach, colorectal, head and neck, larynx, genitourinary, prostate, cervix, bladder, brain metastasis, 1328

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prophylactic cranial radiotherapy’. The screened abstracts and manuscripts language were limited to English. The papers which included the largest case series and data of cases about prophylactic cranial radiotherapy and/or were published in the 10 years before the last search date were selected. If there was no available data about the role of PCI for the specified organ or region in the last 10 years, we selected the largest published case series and trials without considering the publication date. The last search was on 15 October 2013. More than 100 papers had preliminary assessment and 60 papers were selected according to search criteria. All of the 60 papers were evaluated in review. All resulting studies were retrieved and checked for related publications.

Eligible studies Clinical trials in this review fulfilled all of the following criteria: inclusion of sufficient data to allow estimation of the benefit of performing or not performing PCI. The languages of the published clinical trials were restricted to English.

The concept of PCI We will discuss how the concept of PCI is developed for SCLC and EPSCC. The following subsections will summarize the evidence about PCI for each organ site.

PCI for SCLC and EPSCC The vast majority of chemotherapy regimens are not effective for brain parenchyma due to the blood brain barrier. With this barrier the brain gains a special place as a potential ‘pharmacologic sanctuary site’ for metastatic diseases12. The question arises ‘Is there a role for PCI in this sanctuary site?’ The hypothesis that cranial irradiation may prevent clinically relevant metastasis led to several clinical trials. One of the initial reports about the role of PCI for SCLC suggests that the prolongation of survival with the addition of PCI might be restricted to only patients with complete remission13. The initial studies showed reduction of the incidence of cranial metastasis but no improvement in OS14. Arriagada and colleagues showed decreased incidence of cranial metastasis with PCI in those who had complete remission after initial therapy without increased neurological side effects. In this study, the total 2 year rate of brain metastasis decreased from 67% to 40% with PCI but the effect on OS was not statistically significant15. In a multicenter randomized trial, the role of PCI was evaluated for patients with limited stage SCLC who had complete remission after induction therapy. This report showed a large and significant reduction in www.cmrojournal.com ! 2014 Informa UK Ltd

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Table 1. Selected reports of PCI for gastrointestinal SCC. First author

Year

Hussein45 Brenner4

1990 2004

73 64

2004

544

Brenner28 40

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Namikawa Hudson34 Lv29 Chen32 Nakajima33 Meng36 Zhu37 Lu35 Total*

Number of cases

2005 2007 2008 2011 2012 2013 2013 2013

107 16 126 40 18 127 64 1176 2355

Location

Median follow-up time, months (range)

Colon, rectum Esophagus, stomach, gallbladder, pancreas, small bowel, colon, rectum Esophagus, stomach, colon, rectum gallbladder, pancreas, small bowel, ampulla vateri, liver Stomach Esophagus Esophagus Esophagus Esophagus Esophagus Esophagus Esophagus

– 13 (1–107) – a

– (512) 13 (1–104) 13 25 (1–121) 55 (3–76) 18 (2–108) 12 (2–84) –

Brain metastasis at follow-up (%)

Number of patients with PCI

Comments of authors about PCI

None None

NR NR

NA

None

NR

NA 6.2 None None 5.5 5.5 5 NA 21 (0.9%)

None 2 None None None None 1 None 3

NR NR NR NR NR NR NR NR

2.7 10

*A total of 2355 patients are described in Table 1. Among these patients 21 (0.9%) had brain metastasis and only 3 had PCI. NA: not assigned; NR: not recommended. a 45% of patients died before 12 month follow-up period.

Table 2. Selected reports of PCI for genitourinary SCC. Author

Year

Number of cases

Location

Median follow-up time, months (range)

Brain metastasis at follow-up (%)

Number of patients with PCI

Comments of authors about PCI

Papandreou65 Tremont-Lukats63 Hoskins60 Cheng46 Siefker-Radtke48 Viswanathan59 Choong53 Bex49 Lester51 Asmis66 Siefker-Radtke55 Faraj El-Gehani54 El-Gehani62 Carranza52 Total**

2002 2003 2003 2004 2004 2004 2005 2005 2006 2006 2009 2012 2012 2013

36 38 34 64 88 21 44 25 7 22 30 58 27 12 506

Prostate Prostate Cervix Bladder Bladder Cervix Bladder Bladder Bladder Bladder, prostate Bladder Bladder, prostate, urinary tract Cervix, endometrium, ovary, vagina Prostate, bladder, kidney

6 (5–13) – – (436)* 21 (0–22) – (460)z – (1–80) 38 (0.3–14) – (2–84) – (436)g 31 (5–61) – 24 7 26 (11–40)

19.4 15.7 3 None 9 9.5 4.5 None None None 50 1.7 11.1 16.6 44 (8.7%)

None None 10 None None None None None 3 None 1 1 None 2 17

NA NR NR NR NR NR NA NR Recommendeda NR Recommendedb NR NR Recommendedc

NR: not recommended; NA: not assigned. a Controversial, decide on individual basis. b Recommended only for bulky disease at initial diagnosis. c Recommended in selected cases for extensive stage prostate carcinoma in patients who achieve complete response to therapy and for limited stage bladder SCC. *436 months median overall survival reported. z36% of patients were disease-free at 5 years. g Three of the patients remain disease free more than 36 months. **A total of 506 patients are described in Table 2. Among these patients 44 (8.7%) had brain metastasis and 17 had PCI.

brain metastases (HR ¼ 0.44, 95% CI 0.29–0.67), a significant advantage in brain-metastasis-free survival (HR ¼ 0.75, 95% CI 0.58–0.96) and a non-significant OS advantage (HR ¼ 0.86, 95% CI 0.66–1.12)16. Although the extracranial SCLC was controlled with primary treatment, patients had a 60% of risk of brain metastasis within two or three years17,18. A large number of these patients relapsed only in the brain and generally these patients died following the cranial relapse18,19. ! 2014 Informa UK Ltd www.cmrojournal.com

One of the cornerstone studies shows us important data about PCI for SCLC. This is the meta-analysis reported by Auperin and colleagues. They evaluated 987 limited or extensive stage SCLC patients who had complete remission after induction chemotherapy. It was demonstrated that PCI decreased the cumulative incidence of brain metastasis and increased disease free survival (DFS) and OS. The 24 Gy dose of PCI administration can reduce the risk of cranial metastasis by 50%18. It is important to Prophylactic cranial irradiation in EPSCC Yazıcı et al.

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Table 3. Selected reports of PCI for head and neck SCC. First author

Year

Number of cases

Location

Median follow-up time, months (range)

Barker12 Rosenthal70 Franco71 Total*

2003 2004 2012

23 7 1 31

Larynx, pharynx, parathyroid Sinonasal Cervical region

40 (15–89) 82 (6–266) 40

Brain metastasis at follow-up (%)

Number of patients with PCI

41 42 None 12 (38.7%)

None 1 1 2

Comments of authors about PCI Recommend Recommend Recommend

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*A total of 31 patients are described in Table 3. Among these patients 12 (38.7%) had brain metastasis and 2 had PCI.

emphasize that PCI therapy does not increase the risk of pathologic neurological signs and symptoms20. Also it has been reported that PCI treatment in patients with extensive stage SCLC who respond to initial chemotherapy showed reduced risk of cranial metastasis in 1 year (risk ratio ¼ 0.36). In addition to these results, PCI increased the median DFS and OS from 12.0 weeks to 14.7 weeks and 5.4 months to 6.7 months, respectively. The side effects of PCI did not have a statistically significant negative effect on survival. The 1 year survival rate was improved from 13.3% to 27.1% with PCI21. According to current data, SCLC patients who have achieved complete or partial response after chemotherapy with or without radiotherapy treatment should be followed with PCI. The frequency of brain metastasis of SCLC and EPSCC are totally different. EPSCC patients have less frequent brain metastasis compared to SCLC patients10,22. One retrospective single center study compared 11 (17%) patients with EPSCC and 54 (83%) patients with SCLC. They demonstrated that none of EPSCC patients had brain metastasis compared to 11 (20%) in the SCLC patient group. In addition to that, the OS of extensive EPSCC was better compared to extensive SCLC (P ¼ 0.004)10. Although none of the patients had PCI in the small series of Soto and Eisbruch, only one patient had brain metastasis. In this series, most of the patients had distant failure (78%, 14 of 18). According to this report PCI was not necessary11. An Irish national cohort study evaluated the role of PCI in patients with EPSCC. In this cohort, 280 patients with EPSCC were evaluated and most of them had limited stage disease. The frequency of disease according to site of origin was as follows: esophagus (n ¼ 43, 15.4%), cervix (n ¼ 17, 6.0%), bladder (n ¼ 13, 4.6%) and prostate (n ¼ 10, 3.6%). In this study, 18 patients (6.4%) developed brain metastases and 11 (64.7%) of them were treated with whole brain radiotherapy. Among these patients, two who had PCI were still alive, with an OS of 11.1 and 33.8 months, respectively. This study showed that the incidence of brain metastasis was low compared to the incidence of distant metastasis. Also in this study, patients with brain metastasis had a long OS, which highlighted the low rate of mortality related to brain metastasis. In conclusion, due 1330

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to the low incidence of brain metastasis in this patient group the authors of this study do not recommend PCI for patients with EPSCLC23. A Swiss study reviewed 30 patients with EPSCC from their national cohort. Due to the relatively low incidence of brain metastasis (13%) in EPSCC they do not recommend routine use of PCI24. In a single center study, Muller and colleagues review 20 patients with EPSCC. None of the patients had PCI. Only 3 (15%) patients developed brain metastasis. They reported that PCI may be useless for EPSCC but from previous data they commented that PCI may be considered for head and neck SCC25. In Brennan et al.’s trial 120 patients with EPSCC were evaluated. The most common sites were gynecologic (n ¼ 32), gastrointestinal (n ¼ 28), genitourinary (n ¼ 23) and head and neck (n ¼ 19) region. PCI was performed in seven patients, six of whom had limited disease. In this study, PCI was a positive prognostic factor for survival but had no effect on DFS. Therefore, routine use of PCI was not recommended26. Contrary to these results, Eckert and colleagues calculated the number needed to treat for the prevention of cerebral metastases using the relative risk reduction shown for PCI in SCLC27. They evaluated 51 patients with EPSCC localized to gastrointestinal, head and neck, genitourinary, breast and unknown primary site. Of the 51 patients, six had brain metastasis during the time period. They found that fatal cerebral metastases were prevented in one of 13 patients treated with PCI. In light of this result, they advise considering PCI on an individual basis for those with good response to initial treatment27. There are discrepancies between the results of the reports. These databases evaluated EPSCC originating in different regions in the same cohort. We have to ask the question ‘Is there a difference between subgroups of EPSCC?’. Now we will discuss the evidence about PCI for EPSCC by organ site.

PCI for gastrointestinal tract EPSCC The recommendations for PCI in EPSCC can differ due to organ of origin. As we focused site by site, the gastrointestinal tract is the most common site of EPSCC. Brenner and colleagues summarized 64 cases of gastrointestinal SCC; only one of the patients had brain metastasis at admission. www.cmrojournal.com ! 2014 Informa UK Ltd

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Also, during follow-up, 10% of patients had metastasis to the brain which was less commonly involved compared to other organs4. In 2004, a total of 544 gastrointestinal SCC cases were reviewed. The most common locations were esophagus, colon, stomach, gall bladder and rectum, respectively. This review commented that the data were insufficient to advise routine use of PCI for gastrointestinal small cell carcinoma patients28. From May 1985 to June 2005, a Chinese single center study reported the results of 126 consecutive patients with esophageal SCC. Forty-one patients had extensive and 85 had limited disease. The most common site of metastasis was the liver and lymph nodes. In this manuscript, none of the patients had clinically relevant brain metastasis. Probably due to the low incidence of brain metastasis, the institution treatment protocol did not include PCI29. Wu and colleagues reported the records of nine patients with primary esophageal small cell carcinoma30. All of them had primary resection of tumor followed with chemotherapy and none of them had PCI. During the follow-up period, three patients (33.3%) developed concurrent multiple metastases including brain. Due to the small study size, the patients with brain metastasis also had developed distant metastasis, which showed us PCI seemed to be unnecessary in this patient group. Recent registry data demonstrated that out of 10,540 patients with esophageal cancer, 49 (0.005%) were diagnosed with EPSCC. Twenty-six (53%) patients had extensive disease. The study was intended to determine the best treatment for esophageal SCC. Unfortunately, the abstract did not include details about whether their treatment strategies included PCI or not31. One single center institution reported the treatment strategies of 40 patients with limited stage esophageal SCC. Their treatment protocols did not include PCI. Therefore, they did not perform PCI on any of their patients and during follow-up none of the patients developed brain metastasis32. A recent study from Japan retrospectively analyzed nonsurgical approaches to 18 patients with SCC of the esophagus. In this study, treatment strategy did not include PCI. During the follow-up period only one patient (5.5 %) developed brain metastasis. This study verified that PCI for esophagus SCC is unnecessary33. Another single institutional study reported the results of 16 esophageal EPSCC cases in which 38% were limited stage. Two of the patients with limited stage who had partial response to induction chemotherapy were administrated PCI concurrently with radiotherapy (RT) to the esophagus. In this study, only one patient relapsed in the brain, none of the limited stage patients developed brain metastasis34. The study from China analyzed 1176 eligible cases with esophageal SCC. The previous data indicated that brain metastases were uncommon in esophageal SCC in China, which was observed only two of 185 esophageal SCC patients. Therefore, due to the low incidence of brain ! 2014 Informa UK Ltd www.cmrojournal.com

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metastasis of esophageal SCC at presentation and during follow-up, the researchers did not recommend PCI for esophageal SCC35. Another study reviewed 127 limited stage esophageal SCC patients. During the follow-up period only seven patients had brain metastasis. Because of the low incidence of brain metastasis, this study did not recommend performing PCI in limited stage esophageal SCC36. A recent study from China reviewed 64 patients with esophagus SCC. Forty-six patients (71.9%) had limited disease at presentation, 18 patients (28.1%) had extensive disease and none of them had brain metastasis at time of presentation. Three patients (5%) developed brain metastasis during the follow-up period. Only one patient was treated with PCI. Therefore, the investigators concluded that PCI was an unnecessary intervention for esophageal SCC patients37. Most studies and single center reports do not recommend PCI for esophageal EPSCC. In conclusion, cranial metastasis is a very rare clinic entity to be seen at admission and follow-up of patients with esophageal SCC. Therefore, we do not recommend routine use of PCI for esophageal SCC patients. Further, randomized trials are needed to establish algorithms for this issue. Gastric SCC is a rare entity with poor prognosis. Matsui and colleagues retrospectively reported records of 17 patients with gastric small cell carcinoma. All patients underwent subtotal or total gastrectomy followed by adjuvant chemotherapy. None of the patients had PCI. In the follow-up period, an average 14 months later, concomitant brain and solid organ metastasis were detected in five (29.4%) patients, three of whom were treated by palliative radiotherapy to the whole brain38. A Chinese single center study reviewed 27 patients with limited stage gastrointestinal SCC, among them four patients with gastric SCC. The median survival time for patients with SCC of the stomach was 11 months and during the follow-up period none of them had a brain metastasis39. Namikawa and colleagues reviewed 107 patients with gastric small cell carcinoma. The majority of patients were diagnosed at advanced stage and died within 1 year due to multiple distant metastases and recurrence. None of the patients had PCI. Gastric SCC is a highly aggressive and invasive disease with a low OS rate. In conjunction with these results, PCI had no contribution to OS of patients with gastric SCC40. A recent study reported their experience of 19 patients with primary SCC of the stomach or gastroesophageal (GE) junction from a database of 11,603 cases with gastric cancers. Two of the patients presented with stage IV disease with liver and retroperitoneal metastasis. By 10 December 2011, through a median follow-up of 25.5 months, none of the 15 regularly followed patients had a relapse in brain41. The prognosis was reported to be extremely poor because SCC frequently metastasizes to lymph nodes and/or the liver even in an early stage. During the Prophylactic cranial irradiation in EPSCC Yazıcı et al.

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early period of follow-up, gastric small cell carcinoma can early metastasize to the organs and systems out of the brain. This condition is the major problem that determines the survival of these patients. Therefore, we think that PCI does not give additional benefit to patients with gastric SCC. Although the data about cranial metastasis of gastric SCC is insufficient, we do not recommend routine use of PCI for patients with gastric SCC. The small intestine is the one of the rarer sites where SCC can be detected. In the review by Brenner and colleagues only one (0.2%) out of 544 gastrointestinal SCC patients was diagnosed with small intestinal SCC28. SCC of the appendix is an extremely rare and aggressive disease42. PCI is not recommended for small intestinal and appendix SCC since development of brain metastasis is very rare. Colorectal SCC is very rare. El Demellawy and colleagues reported on 10 colorectal SCC patients. In this report, the tumor occurred in the rectum including the anorectal junction in seven patients, two had ascending colon and one had ileocecal SCC. Nine of the ten cases had metastatic disease at time of diagnosis but they did not have brain metastasis43. A Spanish study reported the results of four colon SCC patients who were liver metastatic at time of diagnosis. Two of the four patients died due to widely metastatic disease a short time after diagnosis44. Hussein and colleagues reported that two of 73 cases of colorectal SCC patients had cranial metastasis at admission45. The reported experiences demonstrated a low rate of brain metastasis developed by colorectal SCC and survival was mainly decided by distant metastasis out of the brain. Adding this information together, we concluded that PCI is unnecessary for patients with colorectal SCC. In conclusion, the data is not sufficient to make a decision about the role of PCI for SCC originating from the gastrointestinal system (Table 1). In the literature there have been no randomized trials on PCI in EPSCC. However, based on extensive single center reports, we do not recommend performing PCI for gastrointestinal SCC.

PCI for genitourinary EPSCC As we mentioned, genitourinary SCC, especially bladder and cervix SCC, is the second most common EPSCC. Cheng and colleagues reported on the clinicopathological features of 64 patients with urinary bladder SCC. Although they demonstrated that urinary bladder SCC had poor prognosis, none of the patients develop brain metastasis during the follow-up period46. Pooling analysis of bladder SCC (n ¼ 342) showed that cumulative incidence of brain metastasis was 11%. In the Netherlands Cancer Institute study, four of 51 consecutive patients with limited bladder SCC developed 1332

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brain metastasis. None of the patients received PCI. None of the patients with extensive stage disease developed brain metastasis. Four patients with limited disease developed brain metastasis. These four patients were treated with cranial irradiation. Two of these died of the disease, 3 and 11 months after cranial irradiation and the other two were alive at 36 months and 12 months after cranial irradiation, respectively. In this report, there was no evidence to support the superiority of PCI to cranial irradiation in bladder small cell carcinoma. In this review, PCI was not routinely recommended47. A single center study from MDACC showed that, during the follow-up period, 55 out of 88 patients with bladder small cell carcinoma had metastasis to different sites. Of the 55 patients with metastatic bladder SCC, nine (16%) had brain metastasis. In this study, none of the patients had PCI. Due to the high metastatic potential of bladder SCC to many different organ sites, it seemed PCI was an unnecessary intervention48. Bex and colleagues reported the results of 25 patients with bladder SCC. They did not perform PCI and none of the patients had mortality related to brain metastasis. Unfortunately, in this study the incidence of brain metastasis was not reported49. A single center study analyzed 18 patients with bladder SCC. After a median 19 month (2–128) followup, only one patient had brain metastasis. Fifteen (83%) of 18 patients were dead. None of the patients had PCI. Bladder SCC has poor prognosis with low brain metastasis incidence50. PCI should not be considered as a treatment option. Lester and colleagues administrated PCI to three out of six patients with bladder SCC who achieved complete response with chemotherapy. One of the patients who had PCI developed liver metastasis, two of them were still disease free after 30 months51. A Spanish single center study reported the results of 12 patients with small cell carcinoma of the genitourinary tract, five of them bladder SCC. Two out of five patients with extensive disease had whole brain palliative radiotherapy, one of them with prophylactic intent. The median PFS of patients with extensive disease was 11 months. The prognosis was very poor. For extensive stage patients with bladder SCC, PCI had no additional benefit. However, one of the two patients who had PCI had limited stage bladder SCC. During follow-up, this patient had no cranial relapse. Therefore, according to this study PCI can be recommended on an individual basis for limited stage bladder SCC patients52. In the MDACC study, five (11%) of 44 patients with bladder SCC developed brain metastasis during the follow-up period. None of the patients had PCI53. A 10 year single institution study from Canada reported the results of all genitourinary SCC patients. Fiftyeight patients were identified with primary sites as follows: urinary bladder 35 (60%), prostate 17 (29%) www.cmrojournal.com ! 2014 Informa UK Ltd

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and upper urinary tract 6 (11%). Twenty-seven out of 58 patients had limited disease and only one of them received PCI. Although only one patient had PCI, only one patient in the entire cohort presented with brain metastases as the site of initial relapse54. In contrast, Siefker-Radtke demonstrated that brain metastases were strongly associated with bulky (cT3b) or metastatic disease of bladder SCC at initial diagnosis. In this trial 50% of these patients developed brain metastasis. The authors advised that PCI should be considered for bulky disease at initial diagnosis55. In this phase II trial, once brain metastases developed, the life expectancy of bladder small cell carcinoma was under 2 months55. Based on this evidence, the Canadian Association of Genitourinary Oncologist guidelines offer PCI for patients with limited or extensive stage disease of bladder SCC who had good clinical response to treatment (Level 4 Grade C)56. In spite of this recommendation by the Canadian Association, we thought that current available data limits the routine use of PCI in bladder SCC. However, the ongoing study designed by MDACC is primarily evaluating the effect of PCI on brain metastasis free survival at 1 year in patients with locally advanced/metastatic (i.e. cT3b, pT3b, Nþ, or Mþ) SCC of the urothelium after chemotherapy. PCI is administered to patients within a 4 month period after surgery or completion of chemotherapy. A total dose of 30 Gy PCI is performed 5 days per week for a total of 3 weeks. Chemotherapy responsive patients without brain metastasis proven by cranial computed tomography and magnetic resonance imaging were enrolled in the study group. It was planned to enroll a total of 30 patients in the study population. The secondary end points of the study are effects of PCI on median time to develop brain metastasis and overall survival of local/ metastatic small cell carcinoma of urothelium. The estimated primary completion date of the study is June 201757. We hope that the ongoing study will clarify the some confusing points about the concept of PCI for patients with urinary system SCC. The incidence of brain metastasis of cervix SCC has varied in different series. In the report by Weed and colleagues, three (20%) of 15 patients from 1977 to 1997 developed brain metastasis58. On the other hand, Viswanathan and colleagues reported on 21 patients with SCC of the cervix and none of these patients had only brain metastasis. However, concomitantly two patients had recurrence in brain and lung, suggesting that PCI would be of little benefit (Table 2)59. In a British Columbia series, none of 34 patients with SCC of the cervix had brain metastasis at initial diagnosis. However, during the follow-up period only one patient developed brain metastasis60. Similarly to these studies, a large single center study from India reported 50 cases of cervix SCC. Only one case developed brain metastasis ! 2014 Informa UK Ltd www.cmrojournal.com

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with accompanying liver and bone metastasis. None of the patients had PCI. In this study brain metastasis incidence was very low61. There has been discrepancy between studies. El-Gehani and colleagues showed the results of 27 patients with female genital tract SCC with primary sites as follows: cervix 16 (59%), endometrium 7 (26%), ovary 3 (11%) and vagina 1 (4%). Although none of the patients had PCI, only three patients relapsed in the brain. The brain metastasis as the first site of relapse is relatively low in female genital tract SCC. According to the authors, the role of PCI for female genital tract SCC is unclear62. The data about the role of PCI for female genital tract SCC is confusing. However, current evidence does not support the performance of PCI. We do not recommend routine use of PCI. In the MDACC series, 16,280 prostate cancer patients were evaluated for their cranial metastasis. During the time period, 131 patients had cranial metastasis, 4.5% constituted by patients with prostate SCC. It was shown that six (15.7%) out of 38 patients with prostate SCC had cranial metastasis. The relative risk of brain metastasis from SCC (6 of 38 patients, 16%) was statistically significant compared to risk of adenocarcinoma (119 of 15,359 patients, RR, 20.36; 95% CI, 9.91–41.84). The median interval from diagnosis of prostate cancer to detection of cranial metastasis was 48 months for SCC. Expect for one patient, the remaining 130 cranial metastatic patients had concurrent metastasis to the other parts of body, especially to bones. None of the patients had PCI and among 130 patients with cranial metastasis 21 of them were treated with palliative cranial radiotherapy, including five with stereotactic radiosurgery. After diagnosis of brain metastasis a median 1 month overall survival time was detected. Brain metastasis was seen as a preterm event63. This study showed that prostate SCC has a tendency to metastasize to the brain. Once it has occurred, the patients have limited life expectancy. Therefore, PCI may delay the occurrence of brain metastasis in prostate SCC and increase the DFS time. The results of a 10 year study of a single institution analyzed 12 patients with urinary tract SCC, six of them prostate SCC. In this cohort, two patients had PCI. Of the two patients one was extensive stage prostate SCC responding to systemic chemotherapy treatment. This patient had no relapse in the brain during the follow-up period52. It seemed that the patient was a good candidate for PCI. In another single center study reported by Spiess et al., eight (10%) out of 83 prostate SCC (n ¼ 27) patients developed brain metastasis. In this study, there was no detail reported about cranial radiotherapy64. Papandreou et al. reported their experience of 36 patients with SCC of the prostate. The majority of patients (32 of 36, 89%) had metastatic disease, especially liver (50%) metastatic. Although all of the patients in this study had normal Prophylactic cranial irradiation in EPSCC Yazıcı et al.

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computed tomography scan and magnetic resonance imaging of the brain at the time of diagnosis, during follow-up seven (19%) of 36 patients developed symptomatic brain metastasis in a median time of 6 months. These patients had no PCI65. Asmis et al. reviewed the results of 22 genitourinary SCCs, through them 10 patients had prostate EPSCC who did not have documented cranial metastasis. Consequently, this study did not recommend PCI for patients with prostate SCC66. Like the other EPSCCs, prostate SCC is an aggressive disease and can have potential metastasis to many different organ systems. Generally prostatic SCC developed brain metastasis by hematogenous spread as retrograde metastasis through lymphatic vessels. Many of the mentioned reports showed us that the frequency of brain metastasis of prostate SCC is much higher (16–19%) compared to other counterparts of EPSCC63,65. Also, in one case report of prostate SCC, the patient had multiple brain metastases subsequent to complete response to chemotherapy. The authors comment that PCI may have a role in patients with complete response to chemotherapy67. Due to the relative high frequency of brain metastasis in prostate SCC, we have to consider PCI in highly selected cases of prostate SCC, especially those with complete or nearly complete response to initial chemotherapy treatment (Table 2).

PCI for head and neck SCC As we move to the head and neck region, the larynx is the most common site for EPSCC of the head and neck. Baugh et al. reported that four (7.7%) of 52 patients with laryngeal SCC developed brain metastasis, but not in patients who received PCI68. Ferlito and Friedmann described the cranial metastasis of the head and neck region as an event that signals a terminal situation and infrequently developed. Therefore, Ferlito and Friedmann did not recommend performing PCI for laryngeal SCC69. Barker and colleagues reported 23 cases of head and neck SCC, including 13 cases of laryngeal SCC. In this report, the 2 year and 5 year intracranial metastasis rates were 25% and 44%; brain only metastasis rates were 21% and 41%, respectively12. In contrast to Ferlito and Friedmann, due to the high rate of cranial metastasis Barker and colleagues considered PCI for patients who had complete response to induction therapy. Due to overlap between PCI field and previous head and neck region RT field, this study recommended incorporating the PCI field theoretically in the first radiation field12. Rosenthal treated 72 cases of non-metastatic primary sinonasal neuroendocrine carcinoma, including seven of them with SCC histology. During the follow-up period, three of seven patients with sinonasal SCC developed cranial metastasis. Only one of three patients with long OS 1334

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(disease free at 14.2 years) had received PCI. In this series, all of the patients with SCC died from progressive disease within 4.5 years after diagnosis, with the exception of the single patient (disease free at 14.2 years) who had PCI. According to this data, the authors advised considering PCI for selected patients with head and neck SCC70. One case report of non-sinonasal SCC had PCI concomitantly with locoregional radiotherapy after completion of six cycles of chemotherapy. One year after the completion of therapy the patient achieved complete remission71. Although PCI for head and neck region SCC remains a controversial issue, due to the high incidence of cranial metastasis we recommend performing PCI on selected patients with head and neck SCC. It is important to emphasize that the primary locoregional RT field of sinonasal SCC can overlap with the PCI field. Therefore, it seems best if PCI of the brain can be planned with consideration of any therapeutic radiotherapy treatment to the sinonasal region (Table 3). The benefit of PCI for small cell carcinoma originating from unknown primary is unproven. According to guidelines of unknown primary tumors, patients with solitary cervical lymph node involvement with squamous cell carcinoma can be treated similarly to head and neck squamous cell carcinoma. From the same perspective, one may speculate that, like head and neck cancer SCC, PCI can be recommended for patients with unknown primary site, diagnosed with EPSCC involving the cervical region.

Conclusion Although there are multiple similarities between EPSCC and SCLC, EPSCC is a totally different clinical entity compared to SCLC. Most EPSCC patients have poor prognosis with limited OS. The incidence of brain metastasis for EPSCC patients is not less frequent compared to lung SCC. In the literature, the brain metastasis incidence of EPSCC might vary from 1.7% up to 40%. Although there is a lack of randomized controlled trials seeking the role of PCI in EPSCC, in many patients PCI is not recommended. However, we have to keep in mind that primary head and neck and prostate SCC are exceptions due to the high incidence of cranial metastasis. For selected patients with head and neck SCC, we advise considering PCI on an individual basis. We need further randomized trials evaluated the role of PCI in EPSCC.

Transparency Declaration of funding This study was not funded.

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Declaration of financial/other relationships O.Y., N.Y.O., M.A.N.S., S.A. and N.Z. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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