Hepatocellular carcinoma (HCC) is a major cancer worldwide.[1–3] In HCC endemic areas (e.g., Taiwan), several risk factors have been identified, such as chronic infections of hepatitis C virus (HCV)[4–6] and/or hepatitis B virus (HBV),[7–9] as well as long-term exposure of fine particle pollution (particulate matter ≤ 2.5 μm [PM2.5]). At initial presentation, most HCC patients were diagnosed with locoregionally advanced disease, which prevents from curative managements, such as surgical resection, percutaneous ethanol injection, and radiofrequency ablation (RFA), resulting in persistent high death rates.
For patients with locoregionally advanced disease, several managements may be applied, such as trans-catheter arterial chemoembolization (TACE),[13,14] targeted therapy (e.g., sorafenib), and radiotherapy (RT). In such a condition, RT can be used in conjunction with TACE for patients with or without portal vein thrombosis (PVT). Moreover, RT with stereotactic body radiotherapy (SBRT)[18,19] technique recently showed promising results for managing HCC.[11,20] Generally, however, though RT is one of treatment modalities for treating HCC,[11,21,22] the role of RT is mainly limited in palliative managements for symptoms alleviation and possible tumor control.
Herein, we reported an unresectable bulky HCC patient who was treated with RT alone. A combined RT technique of simultaneously integrated inner-escalated boost (SIEB) and volumetric-modulated arc radiotherapy (VMAT) was used, that is, SIEB-VMAT. After RT, significant symptoms alleviation, durable tumor control (37 months), and a high quality of life were observed.
2 Case report
2.1 Oncologic timeline of intervention and outcome
According to the CARE guideline[23–25] and a previous CARE-compliant report, we constructed an oncologic timeline to demonstrate cancer diagnosis, staging, intervention, and outcome, chronologically (Fig. 1).
2.2 Patient information
At presentation, an 85-year-old male patient complained of multiple progressive symptoms for 1 month, including upper abdomen distention/pain, bilateral lower limbs swelling, easily fatigue, and poor appetite.
On history review, chronic co-infections of hepatitis B virus (HBV) and hepatitis C virus (HCV) were noted for >30 years. No any therapy was prescribed for HCV and HBV till this presentation. And, he denied any breakout episode of hepatitis.
2.3 Physical exam
On physical examination, consciousness was alert, and JOMAC was intact, in terms of judgment, orientation, memory, abstraction, and calculation. Significant jaundice was noted over the skin and conjunctiva. Multiple plaques of ecchymosis over the 4 limbs and trunk were also observed. No enlarged nodes were palpated on the neck, supra-clavicle fossa, axillary, and inguinal regions. Clear breathing sounds were auscultated, bilaterally.
On abdominal examination, abdominal distension with significant tympanic sounds was found. Remarkably, dullness sounds on percussion were confirmed over the right upper quadrant (RUQ) of the abdomen. Mild-to-moderate tenderness over epigastric and RUQ regions was palpated. Moderate pitting edema over bilateral lower limbs was identified, which involved legs and foots.
2.4 Diagnostic assessment
For liver function assessment, Child-Pugh B was classified (a total score = 8),[27,28] in terms of encephalopathy (none, score = 1), ascites (none, score = 1), total bilirubin (1.5 mg/dL, score = 1), albumin (2.6 g/dL, score = 3), and prothrombin time (4 s, score = 2). Note that the level of direct bilirubin was 0.9 mg/dL. In addition, GOT and GPT values were elevated but both within 2-folds of upper limits (76 and 64 IU/L, respectively).
For renal assessment, BUN and creatinine levels were also elevated (28 and 2.2 mg/dL), representing a possibility of mild renal impairment secondary to liver function disturbance.
On images, abdomen computer tomography (CT) showed a bulky liver tumor with size about 12.5 × 10 × 8.5 cm over the caudate lobe of the liver (Fig. 2). Biopsy was done, and pathology reported moderately differentiated hepatocellular carcinoma. After work-up studies, clinical stages were classified as American Joint Committee on Cancer (AJCC)[29–31] stage IIIA (cT3aN0M0) and Barcelona Clinic Liver Cancer (BCLC) stage C. Inoperable condition and unresectable status were recognized based on old age, co-infection of chronic hepatitis B and C virus, impaired liver and renal function, bleeding tendency, and central location of the bulky tumor.
As a result, several treatment modalities could not be prescribed safely, including surgical resection, RFA, TACE, and sorafenib. Thereafter, after discussion with the patient and his family, RT alone was given. A combined technique of SIEB-VMAT was applied by using the Varian Eclipse Treatment Planning System (USA; version 11). For SIEB, doses were painting with prescribed gradience, as follows: the outer plan target volume (PTV), 39 Gy (1.5 Gy × 26 fractions); the middle PTV, 52 Gy (2 Gy × 26 fractions); and, the inner PTV, 57.2 Gy (2.2 Gy × 26 fractions; Fig. 3A-C). The whole RT course was smooth (Fig. 1, from October 2012 to November 2012).
Interestingly and unexpectedly, we found cyproheptadine, a recently identified potential anti-HCC agent,[33–35] was prescribed for alleviating skin itching and allergic rhinitis (2 mg by mouth Q12h; prescribed since the last 2 weeks of the RT course and then persistently used for 24 months).
2.6 Follow-up and outcomes
For HCC-associated symptoms, upper abdominal fullness, poor appetite, and lower limbs edema were improved gradually during and after RT. Remarkably, according to the common toxicity criteria of adverse events (CTCAE) version 4.03, no significant treatment-associated toxicity was found, except for grade 1 fatigue during RT (i.e., relieved after rest). No late RT sequelae were observed till the last follow-up.
For laboratory tests—before, during, and after RT—weekly follow-up GOT/GPT profiles (IU/L) were as follows: 76/64 (before), 74/87 (2nd week), 88/96 (3rd week), 101/118 (4th week), 104/124 (5th week), 47/40 (6th week; the end of RT), and 37/27 (1 month after RT). Follow-up total bilirubin levels were decreased from 1.5 (before) to 0.5 mg/dL (1 month after RT). Creatinine levels were also attenuated from 2.2 (before) to 1.4 mg/dL (1 month after RT). Remarkably, the albumin level was increased from 2.6 g/dL (before) to 3.1 g/dL (1 month after RT). Taken together, these laboratory profiles supported remission of HCC-associated symptoms after RT.
For tumor control, the largest diameter of the viable tumor part was recorded for estimating tumor response according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Simultaneously, auto-calculated tumor volume (c.c.) by the RT planning system (Eclipse Version 11) was also reported in the following CT images.
First, on pre-RT CT, the largest diameter of viable HCC was 12.5 cm (September 2012; size, 12.5 × 10 × 8.5 cm; volume, 608.5 c.c.; Fig. 2). Second, on post-RT CT, the largest diameter of the irradiated viable HCC was 4.9 cm (December 2012; 1 month after RT; size, 4.9 × 4.2 × 3.1 cm; volume, 68.7 c.c.; Fig. 4). As a result, a significant tumor response (partial response [PR]) was noted, with a post-RT volume reduction rate of 88.7%.
More notably, the last follow-up abdominal CT (July 2015, 32 months after RT; tumor volume, 5.8 c.c.; Fig. 5) showed a persistent tumor regression (near-complete response [near CR], with a large volume reduction rate of >99% when compared with the pre-RT bulky tumor).
As a result, after RT with combined SIEB-VMAT technique, a relatively durable progression-free survival with a high quality of life was noted (37 months; from November 2012 to December 2015; Fig. 1 and Fig. 6).
Note that a gradual regeneration of the normal liver is noted after persistent tumor burden reduction (Fig. 4 and Fig. 5, when compared with Fig. 2), supporting that restoration of liver function and alleviation of malignant symptoms are possible after effective anti-HCC treatments.
The main finding: RT with SIEB-VMAT technique was useful in this elderly patient with unresectable bulky HCC; significant tumor volume reduction and durable treatment response resulted in a high quality of life.
Elderly patients with unresectable bulky HCC are still difficult to manage. Many treatment modalities cannot be conducted safely, such as RFA, TACE, and targeted therapy (e.g., sorafenib). As a result, most (if not all) of these patients were excluded from clinical trial candidates, and few items were known about them.
Herein, we reported such an elderly patient with an unresectable bulky HCC. RT with combined SIEB-VMAT technique was given. Surprisingly, significant symptoms alleviation and effective tumor control were noted, resulting in a relatively durable disease-free time interval. Further prospectively clinical trials are encouraged.
Clinical reasoning for applying SIEB-VMAT in this elderly patient with unresectable bulky HCC: maximizing therapeutic gains for double benefits of better tumor control and fewer treatment toxicities.
Simultaneously integrated boost (SIB)[38–40] technique is a well-known modern RT-prescribing technique; it can be used in combination with several RT-irradiating techniques, such as intensity-modified radiotherapy (IMRT)[41–43] and VMAT.[44–46] In the literature, several types of bulky tumors have been irradiated by integrating SIB, such as lung cancer, esophagus cancer, and soft tissue sarcoma. In general, significant tumor volume reduction with a prolong progression-free survival is frequently observed.
Recently, a modified-SIB technique—focusing on intratumor dose escalation—has been reported to induce more significant tumor regression in several unresectable bulky tumors, such as huge pelvic mass, retroperitoneal mass, breast masses, and liver tumors. In the present case, we used a similar modified SIB by incorporating VMAT, i.e., SIEB-VMAT. When compared with the published modified-SIB,[50–52] a similar point was that a larger fraction size is delivered to the geometrically central region of a bulky tumor (in the same treatment fractions), intending to gain a better tumor control.
But differently, we used a smaller fraction size (1.5 Gy; not the conventional 1.8–2.0 Gy per fraction) to the peripheral zone of the irradiating tumor, intending to minimize RT-associated treatment toxicities. In our near 5-year experience, this peri-bulky-tumor dose-attenuation strategy was particularly useful in elderly patients. As shown in the present case, this strategy gained an effective tumor control with a cost of negligible toxicities. We named this modified technique (i.e., combined intratumor dose escalation and extra-tumor dose attenuation) as simultaneously integrated inner-escalated boost (SIEB). This manipulation achieved double benefits in treating elderly patients with bulky tumor: a higher intratumor dose gained a higher tumor control; on the contrary, a lower peripheral tumor dose achieved lower treatment toxicities. As a result, therapeutic gain was largely increased.
The present case showed us that this strategy works well. Further prospective studies are encouraged to explore the actual effective size of this modification, especially in elderly patients or those patients with multicomorbidities.
An incidental finding arising both biology and clinical interesting: whether combined RT with cyproheptadine is able to increase tumor control in HCC is not clear.
The present case harbors an interesting point. That is, though we used SIEB-VMAT to escalate intratumor dose for increasing tumor control, the prescribed inner dose of 57.2 Gy in 26 fractions was not extremely high as that of previous studies (i.e., the inner highest dose of around 90 Gy).[50–52] Thus, whether our observed effective and durable tumor control results from RT itself, a purely intrinsic high radiosensitivity of the irradiated HCC, or a combined effect of other factors is not clear.
In the literature review, we incidentally found a potential anti-HCC agent, that is, cyproheptadine.[33–35] Clinically, cyproheptadine is an antihistamine agent that can be used for managing skin itching, rhinitis, and allergic reaction. It can also be used for increasing appetite in children. Recently, unexpected significant tumor regressions were observed in 2 HCC patients with lung metastasis who were treated with a combination of thalidomide and cyproheptadine. Moreover, in vitro experiments showed a cytotoxic effect of cyproheptadine in 2 HCC cell lines. Further mechanism-exploring experiments demonstrated that cyproheptadine inhibits proliferation of HCC cells via activating P38 kinase to block cell cycle progression. Finally, a small case series reported additional benefits of cyproheptadine in prolonging overall and progression-free survival in advanced HCC patients treated with sorafenib.
In the present case, no thalidomide and sorafenib was used. But, cyproheptadine was retrospectively found to be used in conjunction with RT for covering skin itching and allergic rhinitis (2 mg by mouth Q12h for 2 years; prescribed since the last 2 weeks of RT course). But, mainly due to our relatively lower prescribed dose of cyproheptadine than that of prior reports,[33–35] whether cyproheptadine benefits the present case in terms of tumor control is largely unclear.
However, further prospective studies to test the effect of combined cyproheptadine and RT, particularly SIEB-VMAT, still raise large interests in both biological and clinical aspects.
Gradual normal liver regeneration occurred after durable tumor control of irradiated HCC: restoring liver function and alleviating HCC-associated symptoms
Clinically, liver regeneration is a good sign in treated HCC patients; it may restore, at least partly, impaired liver function and then alleviate malignant symptoms. More notably, liver regeneration may switch an inoperable medical status to an operable condition. In the literature, liver regeneration has been observed after effective treatments of SBRT. The present case confirmed this observation (Figs. 4 and 5, when compared with Fig. 2), reminding us that significant liver regeneration and symptom alleviation are possible if tumor burden of HCC persistently reduced after effective anticancer treatments.
Unresectable bulky HCC patients: survival and outcome comparison among varied available treatments, for example, TACE, targeted therapy, RT, or their combinations.
Till now, managing unresectable HCC patients are still difficult. Several modalities are available, including TACE,[13,14] targeted therapy (e.g., sorafenib), radiotherapy, and most commonly, their combinations.[11,20–22] For example, if medical fit, most of these patients were treated with combined TACE and sorafenib, with a median overall survival ranged from 12 to 27 months. With a cost of frequent adverse events (85.3% [2,732/3,202]), a large observation study recently reported a favored overall survival for patients treated with concomitant-TACE/sorafenib (21.6 months) when compared with those patients treated with nonconcomitant-TACE/sorafenib (9.7 months).
Similar unsatisfied results have also been reported in patients treated with combined TACE and RT. For instance, unresectable HCC patients treated with this combination have been reported to demonstrate a median overall survival of 20.2 months (95% CI, 8.6–31.9 months). When compared with TACE alone, better clinical outcomes of combined TACE and RT are also confirmed in a large meta-analysis, in terms of 1-year survival (odds ratio [OR], 1.36; 95% CI, 1.19–1.54) and complete tumor response (OR, 2.73; 95% CI, 1.95–3.81). More notably, the observed survival benefit is gradually increased from 2 years (OR, 1.55; 95% CI, 1.31–1.85) to 5 years (OR, 3.98; 95% CI, 1.86–8.51).
Although comparing overall survival is largely beyond the scope of a single case report, the present SIEB-VMAT-irradiated patient seemly had a relatively longer survival (42 months; from September 2012 to March 2016) when compared with the other HCC patients who were treated at our institute in the similar period. From 2010 to 2013, our unpublished data showed 3-year overall survival rates of 43.1% for all HCC patients (n = 240; any stage) and 13.7% for patients with AJCC stage III and BCLC stage C (n = 19; these data were externally audited by the National Cancer Center Accreditation and the Taiwan Health Promotion Administration).[58,59] Of the 19 stage-C patients, only 4 patients were treated with a component of RT to their bulky liver tumors. Of the 4 irradiated patients, 2 cases were treated with SIEB-VMAT. One was the present patient who gained relatively good clinical outcomes. But, the other one was immaturely died at the 4th RT fraction due to a lethal bleeding event of rupture of esophagus varices secondary to severe liver cirrhosis.
Strength 1: As mentioned above, in conducting SIB technique, several RT techniques may be used, such as IMRT[41–43] and VMAT.[44–46] In general, when compared with IMRT, VMAT demonstrates a similar target coverage but with a better radiation dosimetric profile. The present case used VMAT to conduct a modified-SIB (i.e., SIEB-VMAT), focusing on both intratumor dose escalation and extra-tumor dose attenuation, achieving a good tumor control with minimized treatment toxicities.
Strength 2: As mentioned above, being different from the prior published modified-SIB,[50–52] our SIEB-VMAT not only focused on simultaneous intratumor dose escalation (from conventional daily dose of 1.8–2.0 Gy up to 2.2–3.0 Gy), but also prescribed extra-tumor dose attenuation (from conventional daily dose of 1.8–2.0 Gy down to 1.2–1.5 Gy, depending on individual conditions).
To our best knowledge, this type of modified SIB has not yet been reported. In our experience, this modification is particularly useful in the following conditions: (1) for bulky tumors that are closely adjacent to critical normal organs, such as lung or small intestine; (2) for recurrent tumors that are largely limited by prior dose–volume constraints, that is, for patients who were treated with reirradiation or even re-reirradiation; or, (3) highly vulnerable cancer patients, such as elderly patients, those with multiple comorbidities, or those with poor performance status.
The present case supported the usefulness of SIEB-VMAT in an elderly patient with unresectable bulky HCC with associated impairments of liver and renal function.
Even the present case was reported in accordance with the CARE guideline,[23–25] an intrinsic limitation is inevitably existed. That is, the present study just reported treatment experience and clinical outcomes from a single patient. The real effective size of SIEB-VMAT and incidence of its treatment toxicities are largely unknown. Thus, interpreting our data should be cautioned. Further prospective studies are recommended, especially randomized trials to compare SIEB-VMAT with conventional VMAT (i.e., no simultaneous intratumor dose escalation). The interaction between RT and cyproheptadine also requires further investigation.
3.3 Generated testable hypotheses
The present case generated 2 testable hypotheses in patients with unresectable bulky HCC, as follows (Table 1).
Hypothesis 1: SIEB-VMAT is able to gain double benefits of higher tumor control and lower (or similar) RT-associated treatment toxicities than that of conventional VMAT.
Hypothesis 2: SIEB-VAMT in conjunction with cyproheptadine is able to prolong progression-free survival and even overall survival.
For managing locally advanced, unresectable, and inoperable HCC, this case shed us a light that RT with SIEB-VMAT technique may be useful. Treatment goals could be achieved in not only alleviating malignant symptoms, but also generating a durable progression-free time interval. Quality of life of the irradiated patient is able to be improved, especially when liver regeneration is observed. Further randomized clinical trials are encouraged to demarcate the real effective size of SIEB-VMAT. The role of cyproheptadine in irradiating HCC patients arises both biological and clinical interests, suggesting further investigation.
4.1 Patient perspective
Before RT, the patient and his families are very anxious for RT due to a deep fear of RT toxicities, especially concerning patient's old age, impaired liver function, and co-infections of HBV & HCV. After our detailed explanation and ensuring, their anxiety decreased thereafter. Thus, after 2 sessions of physician–patient–family conference, the patient and his families agreed RT to the bulky liver tumor, with 2 treatment goals of symptom alleviation (primary goal) and possible tumor control (secondary goal).
During RT, their anxiety further decreased gradually because near no additional toxicities were found after initiation of RT—only mild fatigue that could be relieved after rest was observed. More notably, malignant symptoms that associated with HCC were decreased gradually, such as lower limbs edema and abdominal distension/pain. The visual analog scale (VAS) of pain was decreased with time elapsed: 8 (1st week), 8 (2nd week), 7 (3rd week), 6 (4th week), 3 (5th week), and 1 (6th week; the end of RT). Note that this bulky tumor patient presented right upper abdominal pain, which is an unusual symptom of HCC.
After completion of RT, the patient felt much better than before RT status. Near no more abdominal fullness, pain, and lower limbs edema were found. The patient and his families were satisfied with treatment results of RT.
4.2 Informed consent, ethic statement, and guideline compliant
The present case report was written after both an acquisition of patient's informed consent and an approval of our institute of review board (IRB; approved number: B10204018). The reported process, analysis, and interpretation were also in accordance with the Helsinki Declaration (initially written in 1975 and then revised in 1983) and compliant with the CARE guideline.[23–25]
This study utilizes research data from the Department of Radiation Oncology, Buddhist Dalin Tzu Chi Hospital, Taiwan (grant number: DTCRD101-E-18).
1. Chen W, Zheng R, Baade PD, et al Cancer statistics in China, 2015. CA Cancer J Clin
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin
3. Siegel RL, Fedewa SA, Miller KD, et al Cancer statistics for Hispanics/Latinos, 2015. CA Cancer J Clin
4. Moreira JP, Malta FM, Diniz MA, et al Interferon lambda and hepatitis C virus core protein polymorphisms associated with liver cancer. Virology
5. Lu M, Li J, Rupp LB, et al Hepatitis C treatment failure is associated with increased risk of hepatocellular carcinoma. J Viral Hepat
6. Holmes JA, Chung RT. Viral hepatitis: HCV compartmentalization in HCC: driver, passenger or both? Nat Rev Gastroenterol Hepatol
7. Poh Z, Shen L, Yang HI, et al Real-world risk score for hepatocellular carcinoma (RWS-HCC): a clinically practical risk predictor for HCC in chronic hepatitis B. Gut
8. Teng YC, Shen ZQ, Kao CH, et al Hepatocellular carcinoma mouse models: hepatitis B virus-associated hepatocarcinogenesis and haploinsufficient tumor suppressor genes. World J Gastroenterol
9. Kwak HW, Park JW, Koh YH, et al Clinical characteristics of patients with cryptogenic hepatocellular carcinoma in a hepatitis B virus-endemic area. Liver Cancer
10. Pan WC, Wu CD, Chen MJ, et al Fine Particle Pollution, Alanine Transaminase, and Liver Cancer: A Taiwanese Prospective Cohort Study (REVEAL-HBV). J Natl Cancer Inst
12. Lu LC, Shao YY, Kuo RN, et al Hospital volume of percutaneous radiofrequency ablation is closely associated with treatment outcomes for patients with hepatocellular carcinoma. Cancer
13. Chen BB, Shih IL, Wu CH, et al Comparison of characteristics and transarterial chemoembolization outcomes in patients with unresectable hepatocellular carcinoma and different viral etiologies. J Vasc Interv Radiol
14. Yu SJ. A concise review of updated guidelines regarding the management of hepatocellular carcinoma around the world: 2010–2016. Clin Mol Hepatol
15. Kudo M, Ikeda M, Takayama T, et al Safety and efficacy of sorafenib in Japanese patients with hepatocellular carcinoma in clinical practice: a subgroup analysis of GIDEON. J Gastroenterol
2016; Epub ahead of print.
16. Yu JI, Park JW, Park HC, et al Clinical impact of combined transarterial chemoembolization and radiotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: An external validation study. Radiother Oncol
17. Huo YR, Eslick GD. Transcatheter arterial chemoembolization plus radiotherapy compared with chemoembolization alone for hepatocellular carcinoma: a systematic review and meta-analysis. JAMA Oncol
18. Kirichenko A, Gayou O, Parda D, et al Stereotactic body radiotherapy (SBRT) with or without surgery for primary and metastatic liver tumors. HPB (Oxford)
19. Mahadevan A, Dagoglu N, Mancias J, et al Stereotactic body radiotherapy (SBRT) for intrahepatic and hilar cholangiocarcinoma. J Cancer
20. Kalogeridi MA, Zygogianni A, Kyrgias G, et al Role of radiotherapy in the management of hepatocellular carcinoma: a systematic review. World J Hepatol
21. Kondo Y, Kimura O, Shimosegawa T. Radiation therapy has been shown to be adaptable for various stages of hepatocellular carcinoma. World J Gastroenterol
22. Kalra N, Gupta P, Chawla Y, et al Locoregional treatment for hepatocellular carcinoma: the best is yet to come. World J Radiol
23. Gagnier JJ, Kienle G, Altman DG, et al The CARE guidelines: consensus-based clinical case reporting guideline development. Headache
24. Gagnier JJ, Kienle G, Altman DG, et al The CARE guidelines: consensus-based clinical case reporting guideline development. BMJ Case Rep
2013. 2013doi: 10.1136/bcr-2013-201554.
25. Gagnier JJ, Kienle G, Altman DG, et al The CARE guidelines: consensus-based clinical case report
guideline development. J Clin Epidemiol
26. Kienle GS, Meusers M, Quecke B, et al Patient-centered diabetes care in children: an integrated, individualized, systems-oriented, and multidisciplinary approach. Glob Adv Health Med
27. Pugh RN, Murray-Lyon IM, Dawson JL, et al Transection of the oesophagus for bleeding oesophageal varices. Br J Surg
28. Peng Y, Qi X, Guo X, et al Versus MELD score for the assessment of prognosis in liver cirrhosis: a systematic review and meta-analysis of observational studies. Medicine (Baltimore)
29. Edge SB. American Joint Committee on Cancer. AJCC Cancer Staging Handbook: From the AJCC Cancer Staging Manual. 7th ednNew York: Springer; 2010.
30. Wittekind Ce, Asamura He, Sobin LHe. TNM Atlas: Illustrated Guide to the TNM Classification of Malignant Tumours. 6th ednChichester: Wiley Blackwell; 2014.
31. Springer, Compton CC, Byrd DR, Garcia-Aguilar J, et al AJCC Cancer Staging Atlas: A Companion to the Seventh Editions of the AJCC Cancer Staging Manual and Handbook. 2012.
32. Jihye C, Jinsil S. Application of radiotherapeutic strategies in the BCLC-defined stages of hepatocellular carcinoma. Liver Cancer
33. Feng YM, Feng CW, Chen SY, et al Cyproheptadine
, an antihistaminic drug, inhibits proliferation of hepatocellular carcinoma cells by blocking cell cycle progression through the activation of P38 MAP kinase. BMC Cancer
34. Feng YM, Feng CW, Lu CL, et al Cyproheptadine
significantly improves the overall and progression-free survival of sorafenib-treated advanced HCC patients. Jpn J Clin Oncol
35. Feng YM, Feng CW, Chen SC, et al Unexpected remission of hepatocellular carcinoma (HCC) with lung metastasis to the combination therapy of thalidomide and cyproheptadine
: report of two cases and a preliminary HCC cell line study. BMJ Case Rep
2012; doi: 10.1136/bcr-2012-007180.
36. Health UDo, Services H. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 2010. Washington, DC: US Government Publishing Office; 2015.
37. Sato Y, Watanabe H, Sone M, et al Tumor response evaluation criteria for HCC (hepatocellular carcinoma) treated using TACE (transcatheter arterial chemoembolization): RECIST (response evaluation criteria in solid tumors) version 1.1 and mRECIST (modified RECIST): JIVROSG-0602. Ups J Med Sci
38. Stromberger C, Cozzi L, Budach V, et al Unilateral and bilateral neck SIB for head and neck cancer patients: Intensity-modulated proton therapy, tomotherapy, and RapidArc. Strahlenther Onkol
39. Aly MM, Glatting G, Jahnke L, et al Comparison of breast simultaneous integrated boost (SIB) radiotherapy techniques. Radiat Oncol
40. Stromberger C, Wlodarczyk W, Marnitz S, et al Simultaneous Integrated Boost (SIB): RapidArc and tomotherapy plan comparison for unilateral and bilateral neck irradiation. Anticancer Res
41. Tomasoa NB, Meulendijks D, Nijkamp J, Cats A, Dewit L. Clinical outcome in patients treated with simultaneous integrated boost—intensity modulated radiation therapy (SIB-IMRT) with and without concurrent chemotherapy for squamous cell carcinoma of the anal canal. Acta Oncol
42. Guckenberger M, Kavanagh A, Partridge M. Combining advanced radiotherapy technologies to maximize safety and tumor control probability in stage III non-small cell lung cancer. Strahlenther Onkol
43. Spiotto MT, Weichselbaum RR. Comparison of 3D confromal radiotherapy and intensity modulated radiotherapy with or without simultaneous integrated boost during concurrent chemoradiation for locally advanced head and neck cancers. PLoS One
44. Arnesen MR, Rekstad BL, Stokke C, et al Short-course PET based simultaneous integrated boost for locally advanced cervical cancer. Radiat Oncol
45. Avanzo M, Chiovati P, Boz G, et al Image-guided volumetric arc radiotherapy of pancreatic cancer with simultaneous integrated boost: optimization strategies and dosimetric results. Phys Med
46. Franzese C, Fogliata A, Clerici E, et al Toxicity profile and early clinical outcome for advanced head and neck cancer patients treated with simultaneous integrated boost and volumetric modulated arc therapy. Radiat Oncol
47. Zhang W, Liu C, Lin H, et al Prospective study of special stage II (T2b-3N0M0) non-small-cell lung cancer treated with hypofractionated-simultaneous integrated boost-intensity modulated radiation therapy. J Cancer Res Ther
48. Yu W, Cai XW, Liu Q, et al Safety of dose escalation by simultaneous integrated boosting radiation dose within the primary tumor guided by (18)FDG-PET/CT for esophageal cancer. Radiother Oncol
49. Zhou Y, Xie PM, Dong C, et al Prospective clinical study of pre-operative SIB-IMRT in preparing surgical boundary of extremity soft tissue sarcoma. Eur Rev Med Pharmacol Sci
50. Nomiya T, Akamatsu H, Harada M, et al Modified simultaneous integrated boost radiotherapy for an unresectable huge refractory pelvic tumor diagnosed as a rectal adenocarcinoma. World J Gastroenterol
51. Nomiya T, Akamatsu H, Harada M, et al Modified simultaneous integrated boost radiotherapy for large retroperitoneal malignant tumor: a case report
. Oncol Lett
52. Nomiya T, Akamatsu H, Harada M, et al Modified simultaneous integrated boost radiotherapy for unresectable locally advanced breast cancer: preliminary results of a prospective clinical trial. Clin Breast Cancer
53. Crane CH, Koay EJ. Solutions that enable ablative radiotherapy for large liver tumors: Fractionated dose painting, simultaneous integrated protection, motion management, and computed tomography image guidance. Cancer
54. Farach A, Quesada J, Teh BS. Liver regeneration following repeat SBRT. J Gastrointest Oncol
55. Liu L, Chen H, Wang M, et al Combination therapy of sorafenib and TACE for unresectable HCC: a systematic review and meta-analysis. PLoS One
56. Geschwind JF, Kudo M, Marrero JA, et al TACE treatment in patients with sorafenib-treated unresectable hepatocellular carcinoma in clinical practice: final analysis of GIDEON. Radiology
57. Zhang T, Zhao YT, Wang Z, et al Efficacy and safety of intensity-modulated radiotherapy following transarterial chemoembolization in patients with unresectable hepatocellular carcinoma. Medicine (Baltimore)
59. Hung SK, Lee MS, Chiou WY, et al High incidence of ischemic stroke occurrence in irradiated lung cancer patients: a population-based surgical cohort study. PLoS One
60. Liu J, Ng D, Lee J, et al Chest wall desmoid tumours treated with definitive radiotherapy: a plan comparison of 3D conformal radiotherapy, intensity-modulated radiotherapy and volumetric-modulated arc radiotherapy. Radiat Oncol
61. Popescu CC, Olivotto IA, Beckham WA, et al Volumetric modulated arc therapy improves dosimetry and reduces treatment time compared to conventional intensity-modulated radiotherapy for locoregional radiotherapy of left-sided breast cancer and internal mammary nodes. Int J Radiat Oncol Biol Phys