Hepato-biliary-pancreatic cancers

Liver resection for colorectal metastases in patients with concomitant extrahepatic
disease

Author(s)：: Kazunori Nojiri, Kuniya Tanaka, Mitsuyoshi Ota, Kazuhisa Takeda,
Michio Ueda, Ryusei Matsuyama, Kouichi Taniguchi, Takafumi Kumamoto,
Ryutarou Mori, Kazuya Nakagawa, Yasuhiro Yabushita, Kazuteru Watanabe, Yasushi Ichikawa* and Itaru Endo
Affiliation(s)：: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Yokohama, Japan
*Department of Clinical Oncology, Yokohama City University, Graduate School of Medicine, Yokohama, Japan

INTRODUCTION: Although recognized as poor prognostic factor, concomitant extrahepatic disease (EHD) is no more considered an absolute contraindication to surgery in patients with colorectal liver metastases (CLM). However, the efficacy of liver resection for patients with concomitant EHD on survival and benefit in such patients is still unclear. The aim of this study was to evaluate the long-term outcome of patients undergoing liver resection for CLM in presence of EHD and identify factors associated with prognosis.
METHODS: From 1992 to 2012, 457 patients underwent resection of hepatic colorectal metastases, of whom 84 (18.4%) had concomitant EHD. Among 84 patients, 57 patients (12.5%) underwent resection of EHD, the remaining 27patients (5.9%) could not underwent complete resection of EHD. Clinicopathologic and outcome data were collected. Variables potentially associated with survival were analyzed by univariate and multivariate analyses.
RESULTS: The 5-year overall and disease-free survival rate of patients who underwent liver resection (n=457) were 51.1% and 27.0%, respectively. The 3- and 5-year survival for patients with concomitant EHD (n=84) were 33.5% and 21.0%, respectively, compared with 70.6% and 57.5%, for those without EHD (p< 0.001).
A total number of 95 EHD sites were present in the 84 patients that had concomitant EHD. Most often, EHD was located in the lungs [n= 44(46.3%)]. The second most frequent EHD location was the lymph nodes [n= 21(22.1%)]. Peritoneal metastases were diagnosed in 15 patients (15.8%). Another 7 patients had a recurrence of the primary colorectal tumor (7.4%). Adrenal metastases were present in 3 patients (3.2%), spleen metastases in 2 (2.1%). Metastases to the bone, bladder and port site were present each in 1 patient (1.1%).
Among the patients with EHD (n= 84), univariate analysis of factors potentially associated with survival were: (1) three or fewer liver tumors, (2) maximum liver tumor diameter less than 50mm, (3) R0 liver resection, (4) complete resection of EHD. On multivariate analysis, surgical margin status of liver resection (hazard ratio [HR] = 2.075, p= 0.02) and complete resection of EHD (hazard ratio [HR] = 1.67, p= 0.04) remained predictors of survival.
In 57 patients who underwent resection both CLM and EHD, univariate analysis of factors potentially associated with survival were: (1) maximum liver tumor diameter less than 50mm, (2) R0 liver resection, (3) isolated lung metastases, (4) the total number of metastases (CLM+EHD) of <5. On multivariate analysis, isolated lung metastases (hazard ratio [HR] = 2.560, p= 0.001) and the total number of metastases (CLM+EHD) of <5 (hazard ratio [HR] = 2.574, p= 0.001) remained predictors of survival.
Finally, long-term outcomes were compared between 27 patients with incomplete resection of EHD (liver resection group) and 39 patients with CLM and EHD who received systemic chemotherapy alone instead of surgical resection (chemotherapy group). The median survival time, 1-, and 3-year survival rates for patients in the liver resection group were 21 months, 60.9%, and 20.0%, respectively. Outcome in the liver resection group was better than those in the chemotherapy group. The median survival time, 1-, and 3-year survival rates for patients in the chemotherapy group were 12 months, 56.8%, and 7.2%, respectively.
CONCLUSION: Liver resection for colorectal metastases in patients with concomitant EHD can provide survival benefit. Especially, patients with isolated lung metastases or with four or fewer metastases (CLM+EHD) should be considered for surgery. Even if patients could not complete resection of EHD, aggressive liver resection for CLM might be the treatment of choice because the long-term outcome in these patients was better in those with chemotherapy alone. (578/700 words)

A central surgical review of resectability of optimally-unresectable colorectal liver metastases following neoadjuvant chemotherapy (KSCC 0802)

Author(s)：: Mitsuhisa Takatsuki¹, Susumu Eguchi¹, Shinji Uchida², Masahiko Sakoda³, Ken Shirabe⁴, Toru Beppu⁵, Yasunori Emi⁴, Eiji Oki⁴, Terumitsu Sawai⁶, Shinichi Ueno³, Hideo Baba⁵, Shoji Natsugoe³, Hiroshi Ogata², Shoji Tokunaga⁷, Yoshihiko Maehara⁴
Affiliation(s)：: ¹Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, ²Department of Surgery, Kurume University Medical Center, Kurume, Japan, ³Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan, ⁴Department of Surgery and Science, Kyushu University, Fukuoka, Japan, ⁵Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan, ⁶Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, ⁷ Medical Information Center, Kyushu University Hospital, Fukuoka, Japan

【Background】Kyushu Study group of Clinical Cancer (KSCC) previously reported that safety and efficacy of neoadjuvant chemotherapy with mFOLFOX6+bevacizumab for H2/H3 liver metastases of colorectal cancer (KSCC0802, Samura et al, J Clin Oncol 30:4s, 2012). We carried out a central review for the purpose of obtaining an objective assessment of how resectability changed during treatment. UMIN-ID: 000001308
【Material and methods】From May 2008 to April 2010, 40 patients were registered in multicenter randomized phase 2 trial (KSCC 0802). We reviewed the CT or MRI scans before and after chemotherapy, according to the method of CELIM study (Folprecht G et al. Lancet Oncol 2010; 11: 38-47).
Central surgical review 1: Five independent liver surgeons from 5 different centers of KSCC evaluated the resectability based on the imaging studies (contrast enhanced CT or MRI) before and after chemotherapy, voted for 1.resectable, 2.borderline resectable, 3.chemotherapy preferred, 4.non-resectable, 5.unevaluable. Each surgeon was blind to other surgeon's voting. Also, no information of patient characteristics was provided.
Central surgical review 2: Three surgeons evaluated the resectability based on imaging studies with discussion each other, with provided patient characteristics.
【Results】Paired before and after chemotherapy CT or MRI scans were available 72 scans(36 patients). Central surgical review 1: Before chemotherapy, 13 patients (36.1%) were evaluated as resectable (1. or 2.), while after chemotherapy, 17 patients (47.2%) were evaluated as resectable. Although there was no significant difference, the resectability increased after chemotherapy. There were minor discrepancies in evaluation, between the surgeons.
Central surgical review 2: Before chemotherapy, 4 patients (11.1%) were evaluated as resectable (1. or 2.), while after chemotherapy, 23 patients (63.9%) were evaluated as resectable.
Actually, 16 patients (44.4%) underwent liver resection after chemotherapy in centers of KSCC.
【Conclusions】This evaluation method in Central surgical review 1 was introduced by the CELIM trial, as reliable procedure. The incidence of resectability increased after chemotherapy, according to this evaluation also in Kyushu, Japan.

Interim analysis of a phase II trial of neoadjuvant chemoradiation therapy followed by conventional resection for cholangiocarcinoma

Author(s)：: Katayose Y. ¹, Nakagawa K. ¹, Yoshida H.², Morikawa T.², Hayashi H. ², Okada T.², Mizuma M.², Motoi F. ², Unno M. ²
Affiliation(s)：: 1. Tohoku University Graduate School of Medicine, Integrated Surgery and Oncology, Sendai, JAPAN.
2. Tohoku University Graduate School of Medicine, Hepato-Biliary Pancreatic Surgery, Sendai, JAPAN

Background: Cholangiocarcinoma has one of the worst prognoses among GI tract cancers. To improve the prognosis of cholangiocarcinoma patients, we have applied neoadjuvant chemoradiation therapy followed by conventional resection for possibly resectable cholangiocarcinoma. We published the phase I study (Hepatogastroenterology. 2011;58:1866-72) and showed that neoadjuvant chemoradiation with conventional resection was safe and tolerable. Then, we proceeded Phase II study (P-2). Here, we evaluated P-2 as an interim analysis and compared the P-2 group and 99 patients who were operated on using conventional resection at the same stage and same period as the P-2 group in terms of the perioperative factors and effectiveness.
Material and methods:
Regimen of P-2 was 600mg/m2 of gemcitabine (day 1 and 8 x 2 courses) with external beam radiation therapy (1.8-Gy daily fractions to a total dose of 45 Gy). Patients with histologically or cytologically confirmed adenocarcinoma of the extra- and hilar cholangiocarcinoma were enrolled from 2008 to June 2012 at Tohoku University Hospital. The primary endpoint was the R0-resection rate. We thought the R0-resection rate was 60% referring to our previous data, assumed that it would increase to 80% with neoadjuvant chemoradiation treatment and calculated that the number of samples would be 36 cases under the condition that α was 0.05 and the power of the test was 0.8 (β was 0.2). We determined that the enrollment should be 40 cases assuming 10% of the patients would drop out.
Results: 22 patients were enrolled in P-2. 21 patients received complete chemoradiation. Only one case was not completed because of the adverse event of Grade 3 appetite loss. 19 cases were operated on, and 18 cases were resected. 3 cases were not operated on. 2 cases were progressing disease, and one was heart failure. The R0-resection rate of the P-2 group and conventional resection group was 62%(13 cases out of 22 cases) and 36%(36 cases out of 99 cases), respectively (p<0.05). Intraoperative bleeding, operative duration and hospital stay after surgery were not significant (Table 1), and surgical site infection (SSI) was also not significant.
Conclusions: Neoadjuvant chemoradiation therapy with conventional resection appears to be effective and well tolerated. The study is continuing as scheduled to further evaluate the benefits of this regimen.

TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR) UMIN UMIN000000992 and UMIN000001754

Oral S-1 with concurrent radiotherapy versus S-1 alone in patients with locally
unresectable pancreatic cancer

Author(s)：: Shinchi H1), Takao S2), Maemura K3), Mataki Y3), Kurahara H3), Hiwatashi K3), Ino S3), Sakoda M3), Ueno S4), Natsugoe S3)
Affiliation(s)：: School of Health Sciences1), Frontier Science Research Center2), Department of Gastroenterological Surgery3), and Department of Clinical Oncology4), Kagoshima University, Kagoshima, Japan

Purpose: S-1 is a new oral fluoropyrimidine anticancer agent shown to be effective for pancreatic cancer. In a previous phase I and phase II trial, we have confirmed the efficacy and safety of S-1 combined with radiotherapy in patients with locally advanced and unresectable pancreatic cancer (Br J Cancer 2007; JHBP Sciences 2012). This randomized phase III trial was conducted to evaluate the survival benefit of S-1 combined with radiotherapy compared to S-1 alone. Methods: Eligible patients had locally advanced and unresectable pancreatic cancer without distant metastases, an ECOG performance status of 0-1, adequate organ and marrow functions, and no prior anticancer therapy. Patients were randomized to receive S-1 combined with radiotherapy versus S-1 alone. S-1 was given orally at a dose of 80 mg/m2/day twice daily on days 1 to 21 in both groups. Radiotherapy was delivered in fractions of 1.25 Gy twice daily, 5 days per week for 4 weeks (total dose: 50 Gy in 40 fractions). In both groups, S-1 was administered for 14 days followed by a 14-day rest period as maintenance therapy until disease progression or unacceptable toxicity. The primary endpoint was overall survival. Results: A total of 40 patients were enrolled. Twenty patients received S-1 combined with radiotherapy, and 20 patients received S-1 alone. There was no treatment-related death or grade 4 toxicity in the both groups. Median overall survival of 19.7 months in the S-1 with radiotherapy group was significantly better than 14.9 months in the S-1 alone group (p = 0.073). Survival rates at 1 and 2 years were 79% and 32% in the S-1 with radiotherapy group and 67% and 10% in the S-1 alone group, respectively. Conclusions: Combination therapy with S-1 and radiation is considered a promising, well-tolerated regimen that can be recommended as a more effective treatment compared to S-1 alone for locally advanced pancreatic cancer.

Phase 2 study of FOLFIRINOX as 1st-line therapy for metastatic pancreatic cancer.

Author(s)：: Masafumi Ikeda1, Takuji Okusaka², Akira Fukutomi³, Tatsuya Ioka⁴, Hiroyuki Isayama⁵ , Junji Furuse⁶ , Shinichi Ohkawa⁷, Narikazu Boku⁸
Affiliation(s)：: 1. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East
2. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital
3. Division of Gastrointestinal Oncology, Shizuoka Cancer Center
4. Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases
5. Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo
6. Division of Internal Medicine, Medical Oncology, Kyorin University School of Medicine Hospital
7. Division of Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center
8. Division of Clinical Oncology, St. Marianna University School of Medicine Hospital

Background
FOLFIRINOX regimen, a combination chemotherapy consisting of oxaliplatin (L-OHP), irinotecan (CPT-11), 5-fluorouracil (5-FU) and l-leucovorin (l-LV), demonstrated significant improvements in overall survival (OS) and progression free survival (PFS) compared with gemcitabine in patients (pts) with metastatic pancreatic cancer (MPC) in the PRODIGE 4/ACCORD 11 trial. Consequently, FOLFIRINOX regimen has become one of the standard regimens for the first-line treatment of MPC in the US and EU. However, the efficacy hasn't evaluated in Japanese pts yet. We conducted a phase II study to assess efficacy and safety of FOLFIRINOX regimen in chemotherapy-naive Japanese pts with MPC.

Material and Methods
Main eligibility criteria were histologically or cytologically proven pancreatic adenocarcinoma or adenosquamous carcinoma, adequate bone marrow function, adequate liver and renal function, PS 0 or 1, age 20-75 and chemotherapy-naive. Patients with UGT1A1*6/*6,*28/*28,*6/*28 genotypes, evident ascites or peritoneal metastasis on CT before enrollment, pulmonary fibrosis or interstitial pneumonia, diarrhea (including watery diarrhea) experienced within 3 days prior to enrollment, uncontrolled diabetes mellitus and any serious complication were excluded from the study. Pts enrolled were treated with FOLFIRINOX regimen (day 1: L-OHP, 85 mg/m2, CPT-11, 180 mg/m2, l-LV, 200 mg/m2 and 5-FU, 400 mg/m2 bolus, day 1-3: 5-FU, 2400 mg/m2 continuous infusion) every 2 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was response rate (RR), and all responses were fixed by extramural review. The secondary endpoints were PFS, OS, and the safety.

Results
Thirty six pts were enrolled between June 2011 and September 2012. Final analysis was performed at 1 year after the final patient enrollment. Median age was 61.5 (27-71). M/F were 24/12, PS 0/1 was 21/15. Primary tumor was located in the head of the pancreas in 7 pts. Six pts had a biliary stent at enrollment. Median numbers of cycles administered were 8 cycles (range 1-25). Median relative dose intensities of L-OHP, CPT-11, 5-FU bolus and 5-FU continuous infusion were 71.0%, 69.6%, 15.9% and 80.3% respectively. Doses were reduced in thirty two pts (88.9%). The RR was 38.9% (95% CI, 23.1-56.5). Median time to response was 49 days (range 35-129). Median duration of response was 170 days (range 42-287). Median PFS was 5.6 months. (95% CI, 3.0-7.8). Median OS was 10.7 months (95% CI, 6.9-13.2). The most common grade 3 or 4 toxicities were neutropenia (77.8%), febrile neutropenia (22.2%), thrombocytopenia, anorexia and anemia (11.1%), increased ALT, nausea and diarrhea (8.3%), peripheral neuropathy and increased AST (5.6%). Febrile neutropenia was observed in only cycle 1, but not in subsequent cycles. Fifty three percentage of the pts received G-CSF support. No treatment-related death was noted in this study.

Conclusions
FOLFIRINOX regimen showed favorable results regarding RR (38.9%), PFS (5.6 months) and OS (10.7 months) in Japanese pts with MPC. Although the incidences of grade 3 or 4 neutropenia and febrile neutropenia were high, the safety of FOLFIRINOX regimen was manageable. Our results suggested FOLFIRINOX regimen can be a new first-line standard treatment in Japanese pts with MPC who meet the enrollment criteria in this study.

Outcomes of Gemcitabine and Erlotinib for advanced pancreatic cancer in NCCHE

Author(s)：: Akiko Kuwahara 1　, Akira Shinohara 2　, Misaki Kobayashi 2　, Hiroyuki Okuyama 1　, Hideaki Takahashi 1　, Izumi Ohno 1　, Satoshi Shimizu 1　,Shuichi Mitsunaga 1　,Hideki Funazaki 2　, Takushi Okusaka　3　, Masafumi Ikeda 1
Affiliation(s)：: 1: Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East
2: Pharmacy Division, National Cancer Center Hospital East
3: Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital

BACKGROUND: Erlotinib and gemcitabine combination chemotherapy has become one of the standard treatments for advanced pancreatic cancer, following the results of the global Phase III trial (Moore, 2007) conducted mainly in Western countries. In this study, patients with advanced pancreatic cancer who were treated with erlotinib and gemcitabine combination chemotherapy had better survival rate than those who received gemcitabine alone. In Japan, however, erlotinib and gemcitabine combination chemotherapy has not been widely adopted because of the toxicity and limited survival advantage. The purpose of this study is to clarify the safety and efficacy of erlotinib and gemcitabine combination chemotherapy.
PATIENTS AND METHODS: The study included patients with advanced pancreatic cancer who received erlotinib (100mg/day orally) and gemcitabine (1000 mg/m2 I.V. day 1, 8, and 15 in a 28 day cycle) as first line chemotherapy at our institute from August 2011 to December 2012. We retrospectively evaluated the efficacy and safety of erlotinib and gemcitabine combination chemotherapy. Toxicity was assessed using the National Cancer Institute Common Terminology　Criteria for Adverse Events (version 3.0). The tumor response was assessed using
Response Evaluation Criteria in Solid Tumors (RECIST). Progression free survival (PFS) was estimated using the Kaplan-Meier method
RESULTS: Patient characteristics: A total of 86 patients with advanced pancreatic cancer were included in this study. The median age was 67 years old (range: 34 to 86 years old) and 49 patients (67.0%) were male. The majority (94.0%) of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and most (77.9%) had metastatic disease. The median CA19-9 level was 752 U/mL (range: 0.1 to 453000 U/mL) and the median CEA level was 4.75 ng/mL (range: 0.4 to 255.7 ng/mL). Twenty two (25.6%) patients received biliary drainage before first line chemotherapy.
Toxicity: The most common adverse event observed was a rash (including acneiform dermatitis, erythema, eczema, and pustular rash) in 70.9% of patients. Most patients of rash were mild to moderate; sever rash (Grade 3) was observed in only 1.2% of patients. Other common non-hematological adverse event included anorexia, nausea, fatigue, and stomatitis, but these were generally Grade 1 or 2. Drug induced interstitial lung disease (ILD) had developed in three patients (3.5%); and 1 patient experienced Grade 3 ILD. Most patients experienced hematological toxicity, with Grade 3 or 4 neutropenia, leucopenia and anemia occurring in 17.4%, 34.9% and 5.8% of patients, respectively. Adverse events led to discontinuation of erlotinib in four patients (4.6%). Treatment related death did not occur.
Efficacy:The complete response was observed in 1 (1.2 %) patient and partial responses were in 6 (7.0 %) patients, with the response rate of 8.2 %. Stable disease was observed in 55 patients, with the disease control rate (more than six weeks) of 72.1%. The median PFS was 4.97 months (95% CI, 3.63–5.83).
CONCLUSIONS: Toxicity of erlotinib and gemcitabine combination chemotherapy for patients with advanced pancreatic cancer was acceptable and incidence of ILD was 3.5%, and efficacy was similar in comparison with previous reports. Although a retrospective study, erlotinib and gemcitabine combination chemotherapy is considered to be well tolerated and effective.

Implication of adjuvant surgery for unresectable pancreatic cancer

Author(s)：: Fuyuhiko Motoi ¹, Masamichi Mizuma ¹, Takanori Morikawa ¹, Hiroki Hayashi ¹, Hiroshi Yoshida ¹, Yu Katayose ^{1, 2}, Shin-ichi Egawa ^{1, 3}, Michiaki Unno^{1, 2, 4}
Affiliation(s)：: ¹Dept. of Surg, Div. of HBP Surg, Tohoku Univ. Hosp., ²Div. of Surg. and Oncol, Tohoku Univ., ³Int. Res. Inst. of Disaster Sci, Tohoku Univ,⁴Dept. of Surg, Div. of Gastrointest. Surg, Tohoku Univ.

Background: Recently there had been some reports about the additional resection (adjuvant surgery) after multimodal treatment such as chemotherapy or chemoradiotherapy (CRT) for initially unresectable pancreatic cancer (Satoi S et al, JHPBS 2013).
Aim: Surgical and oncological outcome for adjuvant surgery were explored as a single institutional experience.
Patients and Methods: Patients with pancreatic cancer resected after multimodal therapy for initially unresectable from January 2007 to December 2012 in division of hepato-biliary-pancreatic surgery, department of surgery, Tohoku university hospital were analyzed retrospectively from the clinical database of our institution. Survival was estimated by Kaplan-Meier method.
Results: There were 15 eligible cases with median age 63, ranging 47 to 75 years old, 11 male and 4 female. Nine was located in head and 6 located in body or tail of the pancreas. Unresectability was due to locally advanced with major arterial abutment (superior mesenteric or celiac or common hepatic artery) over 180 degrees of circumference (n=13) and distant metastases (n=2). Before planned surgery, 7 received CRT, 5 received chemotherapy with gemcitabine and S-1 (GS therapy), and remaining 3 received both sequentially. Median duration from initial therapy to resection was 98 days (ranging 44 to 341 days). There was few case of radiologic responder, with only 1 case of partial response (PR), remaining 14 were stable disease (SD) by response evaluation criteria in solid tumors (RECIST) guideline (Response rate is 6.7%). In contrast to low radiologic response rate, decrease in serum CA19-9 level for elevated 12 cases before treatment was observed in 92%(11/12) with median reduction rate 66%, ranging -20 to 99.9%. The reduced maximum standardized uptake value (SUV) in positron emission tomography (PET) was seen in all 3 evaluated cases. Combined resection of major vessels including port-mesenteric vein and celiac axis resection were performed in 7 and 5 cases, respectively. Median time for operation and blood loss was 529 min (ranging 383 min to 777min) and 1250 ml (ranging 350 to 3012 ml) respectively. There was no operative mortality in this series. Median postoperative hospital stay was 23.5 days, ranging 12 to 174 days. Median overall survival and recurrence free survival was 26.5 months, 10.7 months, respectively. R0 resection was performed in 92 %. True R0 resection rate defined by "Normalized serum tumor marker after R0 resection" was observed in 70%. More than half of the cases (8/15) showed node negative confirm by histological examination. Histo-pathological effect of anti-tumor treatment before surgery was evaluable in 12 cases. There were 5 of evaluable 12 cases (42%) with marked pathological response, grade IIB/III according to Evans' classification, which showed more than 50% of tumor destruction of initial tumor area.
Discussion and Conclusion; Adjuvant surgery for selected patients with initially unresectable pancreatic cancer treated by chemotherapy (GS therapy) and/or CRT could be performed with acceptable surgical feasibility, comparing with conventional pancreatectomy for resectable pancreatic cancer. Additional surgery might improve the survival after multimodal treatment based on the data obtained from this retrospective study. Prospective study is needed to clarify the eligibility, optimal timing and modality for this strategy.

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