今日の臨床サポート

悪性リンパ腫:小腸・大腸

著者: 神藤英二1) 防衛医科大学校外科学講座

著者: 橋口陽二郎2) 帝京大学 下部消化管外科

監修: 杉原健一 東京医科歯科大学大学院

著者校正/監修レビュー済:2022/11/09
参考ガイドライン:
  1. 造血器腫瘍診療ガイドライン 2018年版
  1. WHO 分類改訂第4 版(2017)
  1. 画像診断ガイドライン 2021年版
患者向け説明資料

概要・推奨   

  1. sIL2‐Rは腫瘍マーカーとして有用で悪性度規定因子となるが、上昇しない悪性リンパ腫もあることや、ウイルス感染症などで上昇することもあるため注意する(推奨度1O)
  1. PETは悪性リンパ腫の診断において重要な検査と位置づけられている。また、化学療法後においてもPET所見が加味され治療効果判定がなされる(推奨度1S)
  1. 非ホジキンリンパ腫の予後予測因子として、①年齢、②病期、③LDH値、④performance status(PS)、⑤節外性病変数から算出するInternational Prognostic Index(IPI)が用いられる(推奨度1O)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
神藤英二 : 特に申告事項無し[2022年]
橋口陽二郎 : 特に申告事項無し[2022年]
監修:杉原健一 : 講演料(大鵬薬品工業)[2022年]

改訂のポイント:
  1. 定期レビューを行い、治癒切除の成否と予後との関連について追記した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. わが国では悪性リンパ腫の発生頻度は10万人に20人程度とされる。節外性リンパ腫は全体の24~48%であり、腸管原発は節外性リンパ腫のうちの5~15%を占める。
  1. 腸管原発の悪性リンパ腫では平均年齢55歳前後、男女比は2倍程度男性優位である[1][2][3]。部位別発生頻度は、十二指腸8%、空腸6%、回腸20%、回盲部36%、結腸8%、直腸9%、2臓器以上13%とされる。小腸悪性腫瘍における悪性リンパ腫の割合は40%で、大腸悪性腫瘍における割合は0.4%とされる。
問診・診察のポイント  
  1. 症状は腹痛、腫瘤触知、下血、体重減少など多彩であるが、基本的に以下の4つに大別できる。①間欠的腹痛・悪心・嘔吐などの通過障害に関連した症状、②貧血症状や下血などの腫瘍からの出血による症状、③腫瘤触知や圧迫症状などの腫瘍増大に伴う症状、④持続的腹痛や発熱など、腫瘍部の穿孔や穿通に起因する症状で腹膜刺激症状を伴う。
  1. 上記4点について問診および診察(触診・聴診など)を行う。腫瘤が触知できる場合は、部位・大きさ・可動性を確認する。通過障害の有無・腹膜刺激症状の有無・下血の程度は緊急性を評価するうえで重要である。また、体表リンパ節の腫大を確認する。

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文献 

Seok Jin Kim, Chul Won Choi, Yeung-Chul Mun, Sung Yong Oh, Hye Jin Kang, Soon Il Lee, Jong Ho Won, Min Kyoung Kim, Jung Hye Kwon, Jin Seok Kim, Jae-Yong Kwak, Jung Mi Kwon, In Gyu Hwang, Hyo Jung Kim, Jae Hoon Lee, Sukjoong Oh, Keon Woo Park, Cheolwon Suh, Won Seog Kim
Multicenter retrospective analysis of 581 patients with primary intestinal non-hodgkin lymphoma from the Consortium for Improving Survival of Lymphoma (CISL).
BMC Cancer. 2011 Jul 29;11:321. doi: 10.1186/1471-2407-11-321. Epub 2011 Jul 29.
Abstract/Text BACKGROUND: Primary intestinal non-Hodgkin lymphoma (NHL) is a heterogeneous disease with regard to anatomic and histologic distribution. Thus, analyses focusing on primary intestinal NHL with large number of patients are warranted.
METHODS: We retrospectively analyzed 581 patients from 16 hospitals in Korea for primary intestinal NHL in this retrospective analysis. We compared clinical features and treatment outcomes according to the anatomic site of involvement and histologic subtypes.
RESULTS: B-cell lymphoma (n = 504, 86.7%) was more frequent than T-cell lymphoma (n = 77, 13.3%). Diffuse large B-cell lymphoma (DLBCL) was the most common subtype (n = 386, 66.4%), and extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) was the second most common subtype (n = 61, 10.5%). B-cell lymphoma mainly presented as localized disease (Lugano stage I/II) while T-cell lymphomas involved multiple intestinal sites. Thus, T-cell lymphoma had more unfavourable characteristics such as advanced stage at diagnosis, and the 5-year overall survival (OS) rate was significantly lower than B-cell lymphoma (28% versus 71%, P < 0.001). B symptoms were relatively uncommon (20.7%), and bone marrow invasion was a rare event (7.4%). The ileocecal region was the most commonly involved site (39.8%), followed by the small (27.9%) and large intestines (21.5%). Patients underwent surgery showed better OS than patients did not (5-year OS rate 77% versus 57%, P < 0.001). However, this beneficial effect of surgery was only statistically significant in patients with B-cell lymphomas (P < 0.001) not in T-cell lymphomas (P = 0.460). The comparison of survival based on the anatomic site of involvement showed that ileocecal regions had a better 5-year overall survival rate (72%) than other sites in consistent with that ileocecal region had higher proportion of patients with DLBCL who underwent surgery. Age > 60 years, performance status ≥ 2, elevated serum lactate dehydrogenase, Lugano stage IV, presence of B symptoms, and T-cell phenotype were independent prognostic factors for survival.
CONCLUSIONS: The survival of patients with ileocecal region involvement was better than that of patients with involvement at other sites, which might be related to histologic distribution, the proportion of tumor stage, and need for surgical resection.

PMID 21798075
Cuifen Zhang, Xiaohong Zhang, Zeyu Liu, Jiahao Tao, Lizhu Lin, Linzhu Zhai
The impact of surgery on long-term survival of patients with primary intestinal non-Hodgkin lymphomas based on SEER database.
Sci Rep. 2021 Nov 29;11(1):23047. doi: 10.1038/s41598-021-02597-1. Epub 2021 Nov 29.
Abstract/Text Evidence regarding the need for surgery for primary intestinal non-Hodgkin lymphoma (PINHL) patients with chemotherapy is limited and controversial. We aimed to investigate the specific impact of surgery on survival of PINHL patients. Data from PINHL patients (aged > 18 years) with chemotherapy between 1983 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. We concerned about overall survival (OS) and improved cancer-specific survival (CSS). Propensity score matching (PSM) analysis was also used to explore the reliability of the results to further control for confounding factors. Finally, we screened 3537 patients. Multivariate regression analysis showed that patients with surgery and chemotherapy had better OS (hazard ratio [HR] 0.83; 95% confidence interval [CI] 0.75-0.93; p = 0.0009) and CSS (HR 0.87; 95% CI 0.77-0.99; p = 0.0404) compared with the non-operation group after adjusting for confounding factors. After PSM analysis, compared with non-surgery, surgery remained associated with improved OS (HR 0.77; 95% CI 0.68-0.87; p < 0.0001) and improved CSS (HR 0.82; 95% CI 0.72-0.95; p = 0.008) adjusted for baseline differences. In the large cohort of PINHL patients with chemotherapy older than 18 years, surgery was associated with significantly improved OS and CSS before and after PSM analysis.

© 2021. The Author(s).
PMID 34845308
Seok Jin Kim, Hye Jin Kang, Jin Seok Kim, Sung Yong Oh, Chul Won Choi, Soon Il Lee, Jong Ho Won, Min Kyoung Kim, Jung Hye Kwon, Yeung-Chul Mun, Jae-Yong Kwak, Jung Mi Kwon, In Gyu Hwang, Hyo Jung Kim, Jinny Park, Sukjoong Oh, Jooryung Huh, Young Hyeh Ko, Cheolwon Suh, Won Seog Kim
Comparison of treatment strategies for patients with intestinal diffuse large B-cell lymphoma: surgical resection followed by chemotherapy versus chemotherapy alone.
Blood. 2011 Feb 10;117(6):1958-65. doi: 10.1182/blood-2010-06-288480. Epub 2010 Dec 9.
Abstract/Text The aim of this retrospective cohort study was to analyze the impact of surgery on the outcomes and qualities of life (QOL) in patients with intestinal diffuse large B-cell lymphoma (DLBCL). We assessed 345 patients with either localized or disseminated intestinal DLBCL and compared them according to treatment: surgical resection followed by chemotherapy versus chemotherapy alone. In patients with localized disease (Lugano stage I/II), surgery plus chemotherapy yielded a lower relapse rate (15.3%) than did chemotherapy alone (36.8%, P < .001). The 3-year overall survival rate was 91% in the surgery plus chemotherapy group and 62% in the chemotherapy-alone group (P < .001). The predominant pattern in the chemotherapy group was local relapse (27.6%). When rituximab was used with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), there was no improvement of the outcomes in patients treated with primary surgical resection. The QOL of patients who underwent surgery and chemotherapy was lower than chemotherapy alone, but its difference was acceptable. Multivariate analysis showed that surgical resection plus chemotherapy was an independent prognostic factor for overall survival. Surgical resection followed by chemotherapy might be an effective treatment strategy with acceptable QOL deterioration for localized intestinal DLBCL. This study was registered at www.clinicaltrials.gov as #NCT01043302.

PMID 21148334
Abstract/Text Soluble interleukin-2 receptor (sIL-2R) is produced by activated T and B cells, and the level of this receptor is elevated in patients with non-Hodgkin's lymphoma (NHL). The present study demonstrated that the sIL-2R level was high in the following groups of patients with aggressive NHL; those aged > or = 60 yr, those with a poor PS, those in Ann Arbor stage III or IV, and those in the high intermediate or high risk group according to the International Prognostic Index (IPI). Overall survival was significantly poorer when the sIL-2R level was 2000 U/ml or more. In addition, the overall survival of patients in the low (L) and low-intermediate (L-I) risk groups with an sIL-2R level of 3000 U/ml or more was significantly poorer, suggesting that the sIL-2R level could be particularly useful for identifying patients with a poor prognosis among the L and L-I risk groups. Univariate analysis identified some significant prognostic factors, and multivariate analysis of these factors plus the five IPI prognostic factors showed that the sIL-2R level was an independent prognostic indicator. In conclusion, the present findings established that the sIL-2R level is a significant independent prognostic factor in patients with aggressive NHL.

PMID 11168504
Hideko Goto, Hisashi Tsurumi, Masao Takemura, Yoriko Ino-Shimomura, Senji Kasahara, Michio Sawada, Toshiki Yamada, Takeshi Hara, Kenji Fukuno, Naoe Goto, Masataka Okuno, Tsuyoshi Takami, Mitsuru Seishima, Hisataka Moriwaki
Serum-soluble interleukin-2 receptor (sIL-2R) level determines clinical outcome in patients with aggressive non-Hodgkin's lymphoma: in combination with the International Prognostic Index.
J Cancer Res Clin Oncol. 2005 Feb;131(2):73-9. doi: 10.1007/s00432-004-0600-9. Epub 2004 Oct 21.
Abstract/Text PURPOSE: The aim of the present study was to assess the prognostic significance of serum soluble interleukin-2 receptor (sIL-2R) in aggressive non-Hodgkin's lymphoma (NHL).
METHODS: One hundred and thirteen consecutive patients with previously untreated aggressive NHL (diffuse large B-cell lymphoma, 96; peripheral T-cell lymphoma, 17) prospectively participated in this study between 1995 and 2001. The patients were treated with 6-8 cycles of a CHOP or THP (pirarubicin)-COP regimen.
RESULTS: A high serum sIL-2R level (2,000 U/ml and over) at onset was associated with a low complete remission rate. Patients with high sIL-2R had significantly lower survival rates (5-year, 24%) than those with low sIL-2R (under 2,000 U/ml) (74%) (P<0.01). Multivariate analysis employing sIL-2R levels and conventional prognostic factors demonstrated that high sIL-2R, presence of B-symptoms, and advanced age (60 years and older) were significantly unfavorable variables for overall survival. In addition, we attempted to use sIL-2R in combination with the International Prognostic Index (IPI). The patients in the high (H) risk group and those with high sIL-2R in the low-intermediate (LI)/high-intermediate (HI) risk group had significantly lower survival rates than the patients in the low (L) risk group and those with low sIL-2R in the LI/HI risk group (P<0.001).
CONCLUSION: The results suggest that a high serum sIL-2R level predicts a poor prognosis in aggressive NHL and may be a useful biomarker for selecting appropriate treatment when used in combination with the IPI.

PMID 15503137
Rebecca Elstrom, Liang Guan, Gary Baker, Khozaim Nakhoda, Jo-Anne Vergilio, Hongming Zhuang, Stephanie Pitsilos, Adam Bagg, Lisa Downs, Amit Mehrotra, Scott Kim, Abass Alavi, Stephen J Schuster
Utility of FDG-PET scanning in lymphoma by WHO classification.
Blood. 2003 May 15;101(10):3875-6. doi: 10.1182/blood-2002-09-2778. Epub 2003 Jan 16.
Abstract/Text We retrospectively evaluated (18)fluoro-2-deoxyglucose positron emission tomography (FDG-PET) scans in 172 patients with lymphoma and correlated results with pathologic diagnosis using the World Health Organization (WHO) classification system. In total, FDG-PET detected disease in at least one site in 161 patients (94%) and failed to detect disease in 11 patients (6%). The most frequent lymphoma diagnoses were diffuse large B-cell lymphoma (LBCL; n = 51), Hodgkin lymphoma (HL; n = 47), follicular lymphoma (FL; n = 42), marginal zone lymphoma (MZL; n = 12), mantle cell lymphoma (MCL; n = 7), and peripheral T-cell lymphoma (PTCL; n = 5). FDG-PET detected disease in 100% of patients with LBCL and MCL and in 98% of patients with HL and FL. In contrast, FDG-PET detected disease in only 67% of MZL and 40% of PTCL. Comparison with bone marrow biopsies showed that FDG-PET was not reliable for detection of bone marrow involvement in any lymphoma subtype.

PMID 12531812
Norifumi Tsukamoto, Masaru Kojima, Masatoshi Hasegawa, Noboru Oriuchi, Takafumi Matsushima, Akihiko Yokohama, Takayuki Saitoh, Hiroshi Handa, Keigo Endo, Hirokazu Murakami
The usefulness of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) and a comparison of (18)F-FDG-pet with (67)gallium scintigraphy in the evaluation of lymphoma: relation to histologic subtypes based on the World Health Organization classification.
Cancer. 2007 Aug 1;110(3):652-9. doi: 10.1002/cncr.22807.
Abstract/Text BACKGROUND: Although studies comparing conventional imaging modalities with (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) for the detection of lymphoma and although the relations between (18)F-FDG-PET and histologic types were reported previously, most studies were not systematic and involved relatively small numbers of patients.
METHODS: Two hundred fifty-five patients with lymphoma had their disease staged using (18)F-FDG-PET, and 191 of those patients also were assessed using gallium-67 scintigraphy ((67)Ga). Disease sites were identified on a site-by-site basis using computed tomography scans and/or magnetic resonance imaging. The results of these conventional imaging modalities were compared with the results from (8)F-FDG-PET and (67)Ga, and correlations between the imaging results and pathologic diagnoses were evaluated by using the World Health Organization classification system.
RESULTS: Of 913 disease sites in 255 patients, (18)F-FDG-PET identified >97% of disease sites of Hodgkin lymphoma (HL) and aggressive and highly aggressive non-Hodgkin lymphoma. For indolent lymphoma, the detection rate of (18)F-FDG-PET was 91% for follicular lymphoma (FL); 82% for extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, irrespective of plasmacytic differentiation; and approximately 50% for small lymphocytic lymphoma (SLL) and splenic marginal zone lymphoma (SMZL). The results from (67)Ga were similar to those from (18)F-FDG-PET for most histologic subtypes. However, the sensitivity of (67)Ga was unexpectedly poor for FL, for mantle cell lymphoma (MCL), and for the nasal type of natural killer/T-cell lymphoma (NK/T-nasal), ranging from 30% to 38%.
CONCLUSIONS: (18)F-FDG-PET was useful for all histologic subtypes of lymphoma other than SLL and SMZL. Compared with (67)Ga, the authors strongly recommend the use of (18)F-FDG-PET in patients with FL, MCL, and NK-nasal.

(c) 2007 American Cancer Society.
PMID 17582800
Josée M Zijlstra, Gerda Lindauer-van der Werf, Otto S Hoekstra, Lotty Hooft, Ingrid I Riphagen, Peter C Huijgens
18F-fluoro-deoxyglucose positron emission tomography for post-treatment evaluation of malignant lymphoma: a systematic review.
Haematologica. 2006 Apr;91(4):522-9.
Abstract/Text Despite the increasing number of publications concerning 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for post-treatment evaluation of lymphoma and the increasing availability of this novel diagnostic modality, its exact role in response assessment after therapy is still unknown. The aim of this study was to systematically review the literature regarding the diagnostic performance of dedicated FDG-PET in evaluation of first-line therapy of Hodgkin's disease and (aggressive) non-Hodgkin's lymphoma, and to calculate summary estimates of its sensitivity and specificity. The databases of PubMed and Embase were searched for relevant studies up to January 2004. Two reviewers independently assessed the methodological quality of each study. As a valid reference test, histology or follow-up of at least 12 months were accepted. A meta-analysis of the reported sensitivity and specificity of each study was performed. Fifteen studies, involving 705 patients, met the inclusion criteria. The studies had several design deficiencies. The majority of studies did not describe whether the reference test was interpreted without knowledge of the FDG-PET findings. In all studies, there was a description of the spectrum of patients included, i.e. all patients for post-treatment evaluation or only patients with substantial residual masses post-treatment. Pooled sensitivity and specificity for detection of residual disease in Hodgkin's lymphoma were 84% (95% CI 71-9192%) and 90% (95% CI 84-9394%), respectively. For non-Hodgkin's lymphoma, pooled sensitivity and specificity were 72% (95% CI 61-82%), and 100% (95% CI 97-100%), respectively. FDG-PET showed reasonable sensitivity and high specificity for evaluation of first-line therapy in Hodgkin's and in non-Hodgkin's lymphoma. Standardization of procedures is required before implementation in clinical practice.

PMID 16585017
Malik E Juweid, Gregory A Wiseman, Julie M Vose, Justine M Ritchie, Yusuf Menda, James E Wooldridge, Felix M Mottaghy, Eric M Rohren, Norbert M Blumstein, Alan Stolpen, Brian K Link, Sven N Reske, Michael M Graham, Bruce D Cheson
Response assessment of aggressive non-Hodgkin's lymphoma by integrated International Workshop Criteria and fluorine-18-fluorodeoxyglucose positron emission tomography.
J Clin Oncol. 2005 Jul 20;23(21):4652-61. doi: 10.1200/JCO.2005.01.891. Epub 2005 Apr 18.
Abstract/Text PURPOSE: To determine whether a response classification based on integration of fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) into the International Workshop Criteria (IWC) provides a more accurate response assessment than IWC alone in patients with non-Hodgkin's lymphoma (NHL).
PATIENTS AND METHODS: Fifty-four patients with aggressive NHL who underwent FDG-PET and computed tomography 1 to 16 weeks after four to eight cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone were assessed for complete response (CR), unconfirmed CR (CRu), partial response (PR), stable disease (SD), and progressive disease (PD) by the IWC and by integrated IWC and FDG-PET (IWC+PET). Progression-free survival (PFS) was also compared between IWC- and IWC+PET-assigned response designations.
RESULTS: By IWC, 17 patients had a CR, seven had a CRu, 19 had a PR, nine had SD, and two had PD. In comparison, by IWC+PET, 35 patients had a CR, 12 had a PR, six had SD, one had PD, and zero had a CRu. In separate multivariate models, PFS was significantly shorter in patients with PR than in those with a CR using IWC (hazard ratio [HR], 8.9; P = .021) or IWC+PET (HR, 29.7; P = .0003). However, when the two classifications were included in the same multivariate model, only IWC+PET was a statistically significant independent predictor for PFS (P = .008 v P = .72 for IWC). In addition, when patients with a PR by IWC and a CR by IWC+PET were compared with those with a CR by IWC and a CR by IWC+PET, there was no significant difference in PFS (HR, 1.6; P = .72), indicating that IWC+PET identified a subset of IWC-PR patients with a more favorable prognosis.
CONCLUSION: Compared with IWC, the IWC+PET-based assessment provides a more accurate response classification in patients with aggressive NHL.

PMID 15837965
Bruce D Cheson, Beate Pfistner, Malik E Juweid, Randy D Gascoyne, Lena Specht, Sandra J Horning, Bertrand Coiffier, Richard I Fisher, Anton Hagenbeek, Emanuele Zucca, Steven T Rosen, Sigrid Stroobants, T Andrew Lister, Richard T Hoppe, Martin Dreyling, Kensei Tobinai, Julie M Vose, Joseph M Connors, Massimo Federico, Volker Diehl, International Harmonization Project on Lymphoma
Revised response criteria for malignant lymphoma.
J Clin Oncol. 2007 Feb 10;25(5):579-86. doi: 10.1200/JCO.2006.09.2403. Epub 2007 Jan 22.
Abstract/Text PURPOSE: Standardized response criteria are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies.
METHODS: The International Working Group response criteria (Cheson et al, J Clin Oncol 17:1244, 1999) were widely adopted, but required reassessment because of identified limitations and the increased use of [18F]fluorodeoxyglucose-positron emission tomography (PET), immunohistochemistry (IHC), and flow cytometry. The International Harmonization Project was convened to provide updated recommendations.
RESULTS: New guidelines are presented incorporating PET, IHC, and flow cytometry for definitions of response in non-Hodgkin's and Hodgkin's lymphoma. Standardized definitions of end points are provided.
CONCLUSION: We hope that these guidelines will be adopted widely by study groups, pharmaceutical and biotechnology companies, and regulatory agencies to facilitate the development of new and more effective therapies to improve the outcome of patients with lymphoma.

PMID 17242396
Malik E Juweid, Sigrid Stroobants, Otto S Hoekstra, Felix M Mottaghy, Markus Dietlein, Ali Guermazi, Gregory A Wiseman, Lale Kostakoglu, Klemens Scheidhauer, Andreas Buck, Ralph Naumann, Karoline Spaepen, Rodney J Hicks, Wolfgang A Weber, Sven N Reske, Markus Schwaiger, Lawrence H Schwartz, Josee M Zijlstra, Barry A Siegel, Bruce D Cheson, Imaging Subcommittee of International Harmonization Project in Lymphoma
Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma.
J Clin Oncol. 2007 Feb 10;25(5):571-8. doi: 10.1200/JCO.2006.08.2305. Epub 2007 Jan 22.
Abstract/Text PURPOSE: To develop guidelines for performing and interpreting positron emission tomography (PET) imaging for treatment assessment in patients with lymphoma both in clinical practice and in clinical trials.
METHODS: An International Harmonization Project (IHP) was convened to discuss standardization of clinical trial parameters in lymphoma. An imaging subcommittee developed consensus recommendations based on published PET literature and the collective expertise of its members in the use of PET in lymphoma. Only recommendations subsequently endorsed by all IHP subcommittees were adopted.
RECOMMENDATIONS: PET after completion of therapy should be performed at least 3 weeks, and preferably at 6 to 8 weeks, after chemotherapy or chemoimmunotherapy, and 8 to 12 weeks after radiation or chemoradiotherapy. Visual assessment alone is adequate for interpreting PET findings as positive or negative when assessing response after completion of therapy. Mediastinal blood pool activity is recommended as the reference background activity to define PET positivity for a residual mass > or = 2 cm in greatest transverse diameter, regardless of its location. A smaller residual mass or a normal sized lymph node (ie, < or = 1 x 1 cm in diameter) should be considered positive if its activity is above that of the surrounding background. Specific criteria for defining PET positivity in the liver, spleen, lung, and bone marrow are also proposed. Use of attenuation-corrected PET is strongly encouraged. Use of PET for treatment monitoring during a course of therapy should only be done in a clinical trial or as part of a prospective registry.

PMID 17242397
Abstract/Text BACKGROUND: Although many patients with intermediate-grade or high-grade (aggressive) non-Hodgkin's lymphoma are cured by combination chemotherapy, the remainder are not cured and ultimately die of their disease. The Ann Arbor classification, used to determine the stage of this disease, does not consistently distinguish between patients with different long-term prognoses. This project was undertaken to develop a model for predicting outcome in patients with aggressive non-Hodgkin's lymphoma on the basis of the patients' clinical characteristics before treatment.
METHODS: Adults with aggressive non-Hodgkin's lymphoma from 16 institutions and cooperative groups in the United States, Europe, and Canada who were treated between 1982 and 1987 with combination-chemotherapy regimens containing doxorubicin were evaluated for clinical features predictive of overall survival and relapse-free survival. Features that remained independently significant in step-down regression analyses of survival were incorporated into models that identified groups of patients of all ages and groups of patients no more than 60 years old with different risks of death.
RESULTS: In 2031 patients of all ages, our model, based on age, tumor stage, serum lactate dehydrogenase concentration, performance status, and number of extranodal disease sites, identified four risk groups with predicted five-year survival rates of 73 percent, 51 percent, 43 percent, and 26 percent. In 1274 patients 60 or younger, an age-adjusted model based on tumor stage, lactate dehydrogenase level, and performance status identified four risk groups with predicted five-year survival rates of 83 percent, 69 percent, 46 percent, and 32 percent. In both models, the increased risk of death was due to both a lower rate of complete responses and a higher rate of relapse from complete response. These two indexes, called the international index and the age-adjusted international index, were significantly more accurate than the Ann Arbor classification in predicting long-term survival.
CONCLUSIONS: The international index and the age-adjusted international index should be used in the design of future therapeutic trials in patients with aggressive non-Hodgkin's lymphoma and in the selection of appropriate therapeutic approaches for individual patients.

PMID 8141877
Laurie H Sehn, Brian Berry, Mukesh Chhanabhai, Catherine Fitzgerald, Karamjit Gill, Paul Hoskins, Richard Klasa, Kerry J Savage, Tamara Shenkier, Judy Sutherland, Randy D Gascoyne, Joseph M Connors
The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP.
Blood. 2007 Mar 1;109(5):1857-61. doi: 10.1182/blood-2006-08-038257. Epub 2006 Nov 14.
Abstract/Text Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity, with patients exhibiting a wide range of outcomes. The addition of rituximab to CHOP chemotherapy (R-CHOP)has led to a marked improvement in survival and has called into question the significance of previously recognized prognostic markers. Since randomized controlled trials of R-CHOP in DLBCL have included select subgroups of patients, the utility of the International Prognostic Index (IPI) has not been reassessed. We performed a retrospective analysis of patients with DLBCL treated with R-CHOP in the province of British Columbia to assess the value of the IPI in the era of immunochemotherapy. The IPI remains predictive, but it identifies only 2 risk groups. Redistribution of the IPI factors into a revised IPI (R-IPI) provides a more clinically useful prediction of outcome. The R-IPI identifies 3 distinct prognostic groups with a very good (4-year progression-free survival [PFS] 94%, overall survival [OS] 94%), good (4-year PFS 80%, OS 79%), and poor (4-year PFS 53%, OS 55%) outcome, respectively (P < .001). The IPI (or R-IPI) no longer identifies a risk group with less than a 50% chance of survival. In the era of R-CHOP treatment, the R-IPI is a clinically useful prognostic index that may help guide treatment planning and interpretation of clinical trials.

PMID 17105812
Philippe Solal-Céligny, Pascal Roy, Philippe Colombat, Josephine White, Jim O Armitage, Reyes Arranz-Saez, Wing Y Au, Monica Bellei, Pauline Brice, Dolores Caballero, Bertrand Coiffier, Eulogio Conde-Garcia, Chantal Doyen, Massimo Federico, Richard I Fisher, Javier F Garcia-Conde, Cesare Guglielmi, Anton Hagenbeek, Corinne Haïoun, Michael LeBlanc, Andrew T Lister, Armando Lopez-Guillermo, Peter McLaughlin, Noël Milpied, Pierre Morel, Nicolas Mounier, Stephen J Proctor, Ama Rohatiner, Paul Smith, Pierre Soubeyran, Hervé Tilly, Umberto Vitolo, Pier-Luigi Zinzani, Emanuele Zucca, Emili Montserrat
Follicular lymphoma international prognostic index.
Blood. 2004 Sep 1;104(5):1258-65. doi: 10.1182/blood-2003-12-4434. Epub 2004 May 4.
Abstract/Text The prognosis of follicular lymphomas (FL) is heterogeneous and numerous treatments may be proposed. A validated prognostic index (PI) would help in evaluating and choosing these treatments. Characteristics at diagnosis were collected from 4167 patients with FL diagnosed between 1985 and 1992. Univariate and multivariate analyses were used to propose a PI. This index was then tested on 919 patients. Five adverse prognostic factors were selected: age (> 60 years vs < or = 60 years), Ann Arbor stage (III-IV vs I-II), hemoglobin level (< 120 g/L vs > or = 120 g/L), number of nodal areas (> 4 vs < or = 4), and serum LDH level (above normal vs normal or below). Three risk groups were defined: low risk (0-1 adverse factor, 36% of patients), intermediate risk (2 factors, 37% of patients, hazard ratio [HR] of 2.3), and poor risk (> or = 3 adverse factors, 27% of patients, HR = 4.3). This Follicular Lymphoma International Prognostic Index (FLIPI) appeared more discriminant than the International Prognostic Index proposed for aggressive non-Hodgkin lymphomas. Results were very similar in the confirmation group. The FLIPI may be used for improving treatment choices, comparing clinical trials, and designing studies to evaluate new treatments.

PMID 15126323
Amy L Lightner, Evan Shannon, Melinda Maggard Gibbons, Marcia M Russell
Primary Gastrointestinal Non-Hodgkin's Lymphoma of the Small and Large Intestines: a Systematic Review.
J Gastrointest Surg. 2016 Apr;20(4):827-39. doi: 10.1007/s11605-015-3052-4. Epub 2015 Dec 16.
Abstract/Text BACKGROUND: Primary gastrointestinal non-Hodgkin's lymphoma (PGINHL) of small and large intestines is a group of heterogeneous, rare malignancies. Optimal treatment practices remain undefined.
METHODS: A systematic review (2003-2015) was performed to assess tumor characteristics, treatment practices, and treatment outcomes of PGINHL of small and large intestines.
RESULTS: Twenty-eight studies (1658 patients) were included; five focused on follicular lymphoma subtype. Of the non-follicular patients, 59.3% presented with abdominal pain, 37.2% were located in ileocecum, and 53.6% were diffuse large B cell lymphoma subtype. The majority of patients (60.7%) were treated with a combination of surgery and chemotherapy. Forty-three percent of studies concluded an overall survival benefit with surgery; none reported increased postoperative morbidity or mortality. Survival outcomes were not typically stratified by emergent versus elective surgery. Multivariate analysis within individual studies associated B cell lymphoma and ileocecum location with higher survival, while advanced stage and B symptoms were associated with poorer survival. Patients with asymptomatic follicular lymphoma had no progression with a watchful waiting approach.
CONCLUSIONS: The majority of patients with non-follicular small and large intestinal PGINHLs are treated with both chemotherapy and surgery. Although surgery appears to be an important part of the treatment algorithm, definitive statements regarding its survival benefit remain limited due to lack of patient stratification based on timing and indication for surgery.

PMID 26676930
Moran Wang, Shengling Ma, Wei Shi, Yuanyuan Zhang, Shanshan Luo, Yu Hu
Surgery shows survival benefit in patients with primary intestinal diffuse large B-cell lymphoma: A population-based study.
Cancer Med. 2021 May;10(10):3474-3485. doi: 10.1002/cam4.3882. Epub 2021 May 1.
Abstract/Text BACKGROUND: The clinical characteristics and prognosis of primary intestinal diffuse large B-cell lymphoma (PI-DLBCL) are rarely reported. We aimed to explore the role of surgery in patients with PI-DLBCL.
METHODS: Adult PI-DLBCL patients were included from the Surveillance, Epidemiology, and End Results database. The effect of surgery was evaluated by Kaplan-Meier and Cox proportional regression analyses. Propensity score matching (PSM) was used to reinforce our results. Lasso regression was utilized to determine independent risk factors of overall survival (OS) for a nomogram and a novel web-based calculator. The performance of the model was measured via concordance index, receiver operating characteristic curve, and calibration plots in both cohorts.
RESULTS: Overall, 1602 patients with PI-DLBCL were analyzed. Surgery significantly improved survival in both univariate and multivariate analyses (p = 0.007, p < 0.001, respectively). Before PSM, local tumor destruction (LTD) displayed a survival advantage over resection in patients without chemotherapy (p = 0.034). After PSM, surgery was still identified as a beneficial factor for OS (p = 0.0015). However, there was no statistical difference between LTD and resection (p = 0.32). The nomogram for 3-, 5-, and 10-year OS predictions exhibited dependable consistency between internal and external validation.
CONCLUSION: This study approves the beneficial effect of surgery on clinical endpoints in PI-DLBCL patients. For those who are not suitable for resection, LTD may also be a practical option. The predictive nomogram and the web-based calculator could help clinicians individually evaluate the prognosis and optimize personalized treatment decisions for these patients.

© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
PMID 33931950
Yefei Shu, Xiaofeng Xu, Wei Yang, Ling Xu
Surgery plus chemotherapy versus chemotherapy alone in primary intestinal lymphoma: a meta-analysis.
J Int Med Res. 2021 Nov;49(11):3000605211056845. doi: 10.1177/03000605211056845.
Abstract/Text OBJECTIVE: Primary intestinal lymphomas (PILs) are uncommon tumors, but their incidence is increasing. Currently, their management is centered around systemic treatments, such as chemotherapy and radiotherapy, whereas surgery is restricted to selected indications. This meta-analysis aimed to evaluate the role of surgery in PIL treatment.
METHODS: We collected publications comparing surgery plus chemotherapy versus chemotherapy alone in patients with PIL from 2000 to 2021. All trials analyzed the summary odds ratios (ORs) of endpoints, including the 5-year overall survival (OS), 3-year OS, and 3-year progression-free survival rates. Combined pooled ORs were analyzed using fixed- or random-effects models according to heterogeneity.
RESULTS: Six studies were included. Compared with chemotherapy alone, surgery plus chemotherapy was associated with significantly higher 5-year OS [OR = 4.88, 95%confidence interval (CI) = 1.91-12.44, Z = 3.32], 3-year OS (OR = 3.83, 95%CI = 2.33-6.30, Z = 5.30), and 3-year progression-free survival (OR = 3.51, 95%CI = 2.20-5.58, Z = 5.29).
CONCLUSIONS: Surgery plus chemotherapy was associated with better outcomes than chemotherapy alone, especially in the early stages. Therefore, surgery plus chemotherapy may be the preferred strategy for appropriately selected patients with PIL.The protocol for this systematic review was registered at INPLASY (INPLASY202180102) and is available in full (https: //doi.org/10.37766/inplasy2021.8.0102).

PMID 34763562
Ho Sup Lee, Lee Chun Park, Eun Mi Lee, Seong Hoon Shin, Byeong Jin Ye, Sung Yong Oh, Moo Kon Song, Sang Min Lee, Won Sik Lee, Byung Woog Kang, Myung Hee Chang, Seok-Goo Cho, Seung Ah Yahng, Sung-Soo Yoon, Ji-Hyun Kwon, Yang Soo Kim
Comparison of Therapeutic Outcomes Between Surgical Resection Followed By R-CHOP and R-CHOP Alone for Localized Primary Intestinal Diffuse Large B-cell Lymphoma.
Am J Clin Oncol. 2012 Dec 1;. doi: 10.1097/COC.0b013e318271b125. Epub 2012 Dec 1.
Abstract/Text OBJECTIVES:: There is no confirmed treatment strategy for primary intestinal diffuse large B-cell lymphoma (DLBL). In this retrospective study, the purpose is to find an appropriate treatment strategy in patients with primary intestinal DLBL undergoing surgery followed by chemotherapy or chemotherapy alone. METHODS:: Seventy-six patients were newly diagnosed with DLBL and received treatment between March 2004 and June 2011. Forty-seven patients were treated with surgical resection followed by rituximab combined with cyclophosphamide, adriamycin, vincristine, and prednisolone (R-CHOP), and 29 patients were treated with R-CHOP chemotherapy alone. RESULTS:: The characteristics of the patients were as follows: the median age was 56.5 years (range, 15 to 85 y) with a female to male ratio of 1.00:1.45. There was no significant difference in patient characteristics between the 2 groups. The estimated 3-year progression-free survival rates (PFS) and overall survival rates (OS) of surgery followed by R-CHOP (surgery/R-CHOP) and R-CHOP alone (R-CHOP) groups were 92.2% and 74.8% (P=0.009) and 94.2% and 80.7% (P=0.049), respectively. In univariate analysis, significant differences were seen in estimated PFS and OS rates when comparing Lugano stages I and II1 with II2 and IIE (P=0.006 and 0.036), low and low-intermediate risk with high-intermediate risk (P=0.004 and 0.000), and surgery/R-CHOP group with R-CHOP group (P=0.009 and 0.049), respectively. In multivariate analysis, there were no independent predictive factors for survival. CONCLUSIONS:: Patients treated with surgery followed by R-CHOP seemed to have a higher survival rate than those treated with R-CHOP alone. There were no significant prognostic factors for survival, but there were possible prognostic factors such as Lugano stage, International Prognostic Index risk, and treatment modality for PFS and OS.

PMID 23211226
Michael Pfreundschuh, Joerg Schubert, Marita Ziepert, Rudolf Schmits, Martin Mohren, Eva Lengfelder, Marcel Reiser, Christina Nickenig, Michael Clemens, Norma Peter, Carsten Bokemeyer, Hartmut Eimermacher, Anthony Ho, Martin Hoffmann, Roland Mertelsmann, Lorenz Trümper, Leopold Balleisen, Ruediger Liersch, Bernd Metzner, Frank Hartmann, Bertram Glass, Viola Poeschel, Norbert Schmitz, Christian Ruebe, Alfred C Feller, Markus Loeffler, German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)
Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60).
Lancet Oncol. 2008 Feb;9(2):105-16. doi: 10.1016/S1470-2045(08)70002-0. Epub 2008 Jan 15.
Abstract/Text BACKGROUND: Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is used to treat patients with non-Hodgkin lymphoma. Interval decrease from 3 weeks of treatment (CHOP-21) to 2 weeks (CHOP-14), and addition of rituximab to CHOP-21 (R-CHOP-21) has been shown to improve outcome in elderly patients with diffuse large B-cell lymphoma (DLBCL). This randomised trial assessed whether six or eight cycles of R-CHOP-14 can improve outcome of these patients compared with six or eight cycles of CHOP-14.
METHODS: 1222 elderly patients (aged 61-80 years) were randomly assigned to six or eight cycles of CHOP-14 with or without rituximab. Radiotherapy was planned to sites of initial bulky disease with or without extranodal involvement. The primary endpoint was event-free survival; secondary endpoints were response, progression during treatment, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat. The trial is registered on National Cancer Institute website, number NCT00052936 and as EU-20243.
FINDINGS: 3-year event-free survival was 47.2% after six cycles of CHOP-14 (95% CI 41.2-53.3), 53.0% (47.0-59.1) after eight cycles of CHOP-14, 66.5% (60.9-72.0) after six cycles of R-CHOP-14, and 63.1% (57.4-68.8) after eight cycles of R-CHOP-14. Compared with six cycles of CHOP-14, the improvement in 3-year event-free survival was 5.8% (-2.8-14.4) for eight cycles of CHOP-14, 19.3% (11.1-27.5) for six cycles of R-CHOP-14, and 15.9% (7.6-24.2) for eight cycles of R-CHOP-14. 3-year overall survival was 67.7% (62.0-73.5) for six cycles of CHOP-14, 66.0% (60.1-71.9) for eight cycles of CHOP-14, 78.1% (73.2-83.0) for six cycles of R-CHOP-14, and 72.5% (67.1-77.9) for eight cycles of R-CHOP-14. Compared with treatment with six cycles of CHOP-14, overall survival improved by -1.7% (-10.0-6.6) after eight cycles of CHOP-14, 10.4% (2.8-18.0) after six cycles of R-CHOP-14, and 4.8% (-3.1-12.7) after eight cycles of R-CHOP-14. In a multivariate analysis that used six cycles of CHOP-14 without rituximab as the reference, and adjusting for known prognostic factors, all three intensified regimens improved 3-year event-free survival (eight cycles of CHOP-14: RR [relative risk] 0.76 [0.60-0.95], p=0.0172; six cycles of R-CHOP-14: RR 0.51 [0.40-0.65], p<0.0001; eight cycles of R-CHOP-14: RR 0.54 [0.43-0.69], p<0.0001). Progression-free survival improved after six cycles of R-CHOP-14 (RR 0.50 [0.38-0.67], p<0.0001), and eight cycles of R-CHOP-14 (RR 0.59 [0.45-0.77], p=0.0001). Overall survival improved only after six cycles of R-CHOP-14 (RR 0.63 [0.46-0.85], p=0.0031). In patients with a partial response after four cycles of chemotherapy, eight cycles were not better than six cycles.
INTERPRETATION: Six cycles of R-CHOP-14 significantly improved event-free, progression-free, and overall survival over six cycles of CHOP-14 treatment. Response-adapted addition of chemotherapy beyond six cycles, though widely practiced, is not justified. Of the four regimens assessed in this study, six cycles of R-CHOP-14 is the preferred treatment for elderly patients, with which other approaches should be compared.

PMID 18226581
Daniel O Persky, Joseph M Unger, Catherine M Spier, Baldassarre Stea, Michael LeBlanc, Matthew J McCarty, Lisa M Rimsza, Richard I Fisher, Thomas P Miller, Southwest Oncology Group
Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014.
J Clin Oncol. 2008 May 10;26(14):2258-63. doi: 10.1200/JCO.2007.13.6929. Epub 2008 Apr 14.
Abstract/Text PURPOSE: To evaluate the effect of rituximab in limited-stage diffuse large B-cell lymphoma (DLBCL), we conducted a multicenter phase II trial combining rituximab with three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) followed by involved-field radiation therapy (IFRT).
PATIENTS AND METHODS: Southwest Oncology Group (SWOG) study S0014 enrolled patients with newly diagnosed, aggressive, CD20-expressing non-Hodgkin's lymphoma (NHL). Patients had limited-stage disease and at least one adverse risk factor as defined by the stage-modified International Prognostic Index (nonbulky stage II disease, age > 60 years, WHO performance status of 2, or elevated serum lactate dehydrogenase). Four doses of rituximab were infused on days -7, 1, 22, and 43, and CHOP was administered on days 3, 24, and 45, followed 3 weeks later by 40 to 46 Gy of IFRT.
RESULTS: Sixty patients with aggressive NHL were eligible. With the median follow-up of 5.3 years, treatment resulted in a progression-free survival (PFS) of 93% at 2 years and 88% at 4 years. Overall survival (OS) was 95% at 2 years and 92% at 4 years. These results were compared with those from a historic group of patients treated without rituximab on S8736, demonstrating PFS of 78% and OS of 88% at 4 years.
CONCLUSION: In limited-stage DLBCL, the addition of rituximab to three cycles of CHOP plus IFRT met prespecified study criteria of efficacy, with 2-year PFS of at least 84%, meriting further investigation. There is a pattern of continuing relapse with modest survival gains. We hypothesize that such a pattern may be the result of biologic differences between limited- and advanced-stage lymphoma.

PMID 18413640
T P Miller, S Dahlberg, J R Cassady, D J Adelstein, C M Spier, T M Grogan, M LeBlanc, S Carlin, E Chase, R I Fisher
Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma.
N Engl J Med. 1998 Jul 2;339(1):21-6. doi: 10.1056/NEJM199807023390104.
Abstract/Text BACKGROUND: Patients with clinically localized, intermediate- or high-grade non-Hodgkin's lymphoma usually receive initial treatment with a doxorubicin-containing regimen such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Pilot studies suggest that eight cycles of CHOP alone or three cycles of CHOP followed by involved-field radiotherapy are effective in such patients.
METHODS: We compared these two approaches in a prospective, randomized, multi-institutional study. The end points were progression-free survival, overall survival, and life-threatening or fatal toxic effects. Two hundred eligible patients were randomly assigned to receive CHOP plus radiotherapy, and 201 received CHOP alone.
RESULTS: Patients treated with three cycles of CHOP plus radiotherapy had significantly better progression-free survival (P=0.03) and overall survival (P=0.02) than patients treated with CHOP alone. The five-year estimates of progression-free survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 77 percent and 64 percent, respectively. The five-year estimates of overall survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 82 percent and 72 percent, respectively. The adverse effects included one death in each treatment group. Life-threatening toxic effects of any type were seen in 61 of 200 patients treated with CHOP plus radiotherapy and in 80 of 201 patients treated with CHOP alone (P=0.06). The left ventricular function was decreased in seven patients who received CHOP alone, whereas no cardiac events were recorded in the group receiving CHOP plus radiotherapy (P=0.02).
CONCLUSIONS: Three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone for the treatment of localized intermediate- and high-grade non-Hodgkin's lymphoma.

PMID 9647875
M S Czuczman, A J Grillo-López, C A White, M Saleh, L Gordon, A F LoBuglio, C Jonas, D Klippenstein, B Dallaire, C Varns
Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy.
J Clin Oncol. 1999 Jan;17(1):268-76.
Abstract/Text PURPOSE: To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody, Rituxan (Rituximab, IDEC-C2B8; IDEC Pharmaceuticals Corporation, San Diego, CA), and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy.
PATIENTS AND METHODS: Forty patients with low-grade or follicular B-cell non-Hodgkin's lymphoma received six infusions of Rituxan (375 mg/m2 per dose) in combination with six doses of CHOP chemotherapy.
RESULTS: The overall response rate was 95% (38 of 40 patients). Twenty-two patients experienced a complete response (55%), 16 patients had a partial response (40%), and two patients, who received no treatment, were classified as nonresponders. Medians for duration of response and time to progression had not been reached after a median observation time of 29 + months. Twenty-eight of 38 assessable patients (74%) continued in remission during this median follow-up period. The most frequent adverse events attributable to CHOP were alopecia (38 patients), neutropenia (31 patients), and fever (23 patients). The most frequent events attributed to Rituxan were fever and chills, observed primarily with the first infusion. No quantifiable immune response to the chimeric antibody was detected. In a subset of 18 patients, the bcl-2 [t(14;18)] translocation was positive in eight patients; seven of these patients had complete remissions and converted to polymerase chain reaction (PCR) negativity by completion of therapy.
CONCLUSION: This is the first report demonstrating the safety and efficacy of Rituxan anti-CD20 chimeric antibody in combination with standard-dose systemic chemotherapy in the treatment of indolent B-cell lymphoma. The clinical responses suggest an additive therapeutic benefit for the combination with no significant added toxicity. The conversion of bcl-2 from positive to negative by PCR in blood and/or marrow suggests possible clearing of minimal residual disease not previously demonstrated by CHOP chemotherapy alone.

PMID 10458242
Myron S Czuczman, Robin Weaver, Baha Alkuzweny, Judy Berlfein, Antonio J Grillo-López
Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up.
J Clin Oncol. 2004 Dec 1;22(23):4711-6. doi: 10.1200/JCO.2004.04.020. Epub 2004 Oct 13.
Abstract/Text PURPOSE: Long-term follow-up with updated time to disease progression (TTP) and duration of response (DR) data are presented from a multicenter, phase II trial of rituximab/cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) combination therapy in 40 patients with CD20+, B-cell, non-Hodgkin's lymphoma (NHL). Revised response rates based on International Workshop Response Criteria are also provided.
PATIENTS AND METHODS: Enrollment began in April 1994 and consisted of patients with histologically confirmed, low-grade, B-cell lymphoma who had received no prior chemotherapy or who had no more than four prior standard therapies. Patients received six cycles of CHOP and six infusions of rituximab.
RESULTS: Eight (21%) of the 38 treated patients were classified as International Working Formulation (IWF) A, 16 (42%) were IWF B, 13 (34%) were IWF C, and one (3%) was IWF D. Nine (24%) of 38 patients had received prior chemotherapy. Nine (24%) of 38 were considered poor risk according to the Follicular Lymphoma International Prognostic Index. Overall response rate was 100%; 87% of patients achieved a complete response or unconfirmed complete response. The median TTP and DR were 82.3 months and 83.5 months, respectively. Seven of eight patients who were bcl-2 positive at baseline converted to negative, and three of the seven patients have sustained the molecular remission.
CONCLUSION: Although a cure has not been found yet for follicular NHL, the R-CHOP combination provides a lengthy response duration in patients with relapsed or newly diagnosed indolent NHL.

PMID 15483015
Robert Marcus, Kevin Imrie, Andrew Belch, David Cunningham, Eduardo Flores, John Catalano, Philippe Solal-Celigny, Fritz Offner, Jan Walewski, Joäo Raposo, Andrew Jack, Paul Smith
CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma.
Blood. 2005 Feb 15;105(4):1417-23. doi: 10.1182/blood-2004-08-3175. Epub 2004 Oct 19.
Abstract/Text The combination of cyclophosphamide, vincristine, and prednisone (CVP) is one of several standard treatment options for advanced follicular lymphoma. This, like similar chemotherapeutic regimens, induces response rates of 60% to 80%, with a median response duration of under 2 years. Rituximab, a chimeric monoclonal antibody against CD20, is active in follicular lymphoma, both as monotherapy and in combination with chemotherapy. Previously untreated patients with stages III to IV follicular lymphoma were randomly assigned to receive either 8 cycles of CVP plus rituximab (R-CVP; n = 162) or CVP (n = 159). Overall and complete response rates were 81% and 41% in the R-CVP arm versus 57% and 10% in the CVP arm, respectively (P < .0001). At a median follow-up of 30 months, patients treated with R-CVP had a very significantly prolonged time to progression (median 32 months versus 15 months for CVP; P < .0001). Median time to treatment failure was 27 months in patients receiving R-CVP and 7 months in the CVP arm (P < .0001). Rituximab did not add significantly to the toxicity of CVP. The addition of rituximab to the CVP regimen significantly improves the clinical outcome in patients with previously untreated advanced follicular lymphoma, without increased toxicity.

PMID 15494430
Brad S Kahl, Fangxin Hong, Michael E Williams, Randy D Gascoyne, Lynne I Wagner, John C Krauss, Thomas M Habermann, Lode J Swinnen, Stephen J Schuster, Christopher G Peterson, Mark D Sborov, S Eric Martin, Matthias Weiss, W Christopher Ehmann, Sandra J Horning
Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402.
J Clin Oncol. 2014 Oct 1;32(28):3096-102. doi: 10.1200/JCO.2014.56.5853. Epub 2014 Aug 25.
Abstract/Text PURPOSE: In low-tumor burden follicular lymphoma (FL), maintenance rituximab (MR) has been shown to improve progression-free survival when compared with observation. It is not known whether MR provides superior long-term disease control compared with re-treatment rituximab (RR) administered on an as-needed basis. E4402 (RESORT) was a randomized clinical trial designed to compare MR against RR.
PATIENTS AND METHODS: Eligible patients with previously untreated low-tumor burden FL received four doses of rituximab, and responding patients were randomly assigned to either RR or MR. Patients receiving RR were eligible for re-treatment at each disease progression until treatment failure. Patients assigned to MR received a single dose of rituximab every 3 months until treatment failure. The primary end point was time to treatment failure. Secondary end points included time to first cytotoxic therapy, toxicity, and health-related quality of life (HRQOL).
RESULTS: A total of 289 patients were randomly assigned to RR or MR. With a median follow-up of 4.5 years, the estimated median time to treatment failure was 3.9 years for patients receiving RR and 4.3 years for those receiving MR (P = .54). Three-year freedom from cytotoxic therapy was 84% for those receiving RR and 95% for those receiving MR (P = .03). The median number of rituximab doses was four patients receiving RR and 18 for those receiving MR. There was no difference in HRQOL. Grade 3 to 4 toxicities were infrequent in both arms.
CONCLUSION: In low-tumor burden FL, a re-treatment strategy uses less rituximab while providing disease control comparable to that achieved with a maintenance strategy.

© 2014 by American Society of Clinical Oncology.
PMID 25154829
Akira Tari, Hideki Asaoku, Katsuyoshi Takata, Shunji Fujimori, Shinji Tanaka, Megumu Fujihara, Tadashi Koga, Tadashi Yoshino
The role of "watch and wait" in intestinal follicular lymphoma in rituximab era.
Scand J Gastroenterol. 2016 Mar;51(3):321-8. doi: 10.3109/00365521.2015.1087589. Epub 2015 Sep 18.
Abstract/Text OBJECTIVE: There is no consensus regarding the best treatment for intestinal follicular lymphoma (FL). We used "watch and wait" for patients with intestinal FL with low-tumor-burden (LTB) criteria and without mass formation causing bowel obstruction. We investigated the overall survival (OS) and time to treatment required (TTR).
METHODS: Thirty-three intestinal FL patients [clinical stage (CS) I:16, II1:0, II2:7, IV:10; median observation period: 45.5 months, range: 13-110 months] were diagnosed via endoscopy. Detailed clinical and pathological examinations were performed, and neoplastic process behavior was monitored.
RESULTS: All of the 33 patients were WHO grade 1. FL lesions in the digestive tract were found frequently in the second-fourth portion of the duodenum in 91% of the patients; 87% of those patients had lesions in a broader area including the small intestine. Two patients had an enlargement of the area of the lesions and a worsening of the macroscopic findings. Three patients had CS progression; however, these remained within the indication for "watch and wait." Two patients with transformation into diffuse large B-cell lymphoma received rituximab and chemotherapy, which led to complete remission. The OS was 100%. The time to treatment required (TTR) was 49 months in one patient and 37 months in one patient.
CONCLUSION: Intestinal FL in CS I-IV with broad infiltration of the digestive tract meeting the criteria for LTB had a remarkably slow course. This study suggests that "watch and wait" is appropriate for the treatment of LTB intestinal FL even in the era of rituximab.

PMID 26382560
Severin Daum, Reiner Ullrich, Walter Heise, Bettina Dederke, Hans-Dieter Foss, Harald Stein, Eckhard Thiel, Martin Zeitz, Ernst-Otto Riecken
Intestinal non-Hodgkin's lymphoma: a multicenter prospective clinical study from the German Study Group on Intestinal non-Hodgkin's Lymphoma.
J Clin Oncol. 2003 Jul 15;21(14):2740-6. doi: 10.1200/JCO.2003.06.026.
Abstract/Text PURPOSE: Intestinal non-Hodgkin's lymphomas are not well characterized. We therefore studied prospectively their clinical features and response to standardized therapy.
PATIENTS AND METHODS: Fifty-six patients with primary intestinal lymphoma were included in a prospective, nonrandomized multicenter study. Lymphoma resection was recommended and staging was performed according to the Ann Arbor classification. Patients were scheduled to receive six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy, and at stages EIII to EIV, they received additional involved-field radiotherapy. Corticosteroids were used in patients who could not receive chemotherapy.
RESULTS: Thirty-five patients had intestinal T-cell lymphoma (ITCL), 21 patients had intestinal B-cell lymphoma (IBCL; 18 diffuse large-cell lymphomas, two marginal-cell lymphomas, and one follicle-center lymphoma). Thirty-four patients at stages EI to EII (14 ITCL and 20 IBCL) and nine patients at stages EIII to EIV (all ITCL) received chemotherapy. No patient in stages EIII to EIV received radiotherapy, because death occurred in 12 of 14 patients. Two-year cumulative survival in patients with IBCL was 94% (95% CI, 82% to 100%) and higher than in patients with ITCL (28% [95% CI, 13% to 43%]; P <.0001), even when only stages EI to EII were considered (ITCL, 37.5% [95% CI, 16.5% to 58.5%]; P <.0001). IBCL patients compared with ITCL patients were at lower lymphoma stages (P <.01), had higher Karnofsky status (P <.005), had intestinal perforation less often (P <.05), required emergency operation less often (P <.05), received CHOP (P <.05) more often, and reached complete remission (P <.0005) more frequently.
CONCLUSION: IBCL patients at stages EI and EII respond well to chemotherapy, but the prognosis and treatment of ITCL patients is unsatisfactory.

PMID 12860953
R Vaidya, T M Habermann, J H Donohue, K M Ristow, M J Maurer, W R Macon, J P Colgan, D J Inwards, S M Ansell, L F Porrata, I N Micallef, P B Johnston, S N Markovic, C A Thompson, G S Nowakowski, T E Witzig
Bowel perforation in intestinal lymphoma: incidence and clinical features.
Ann Oncol. 2013 Sep;24(9):2439-43. doi: 10.1093/annonc/mdt188. Epub 2013 May 22.
Abstract/Text BACKGROUND: Perforation is a serious life-threatening complication of lymphomas involving the gastrointestinal (GI) tract. Although some perforations occur as the initial presentation of GI lymphoma, others occur after initiation of chemotherapy. To define the location and timing of perforation, a single-center study was carried out of all patients with GI lymphoma.
PATIENTS AND METHODS: Between 1975 and 2012, 1062 patients were identified with biopsy-proven GI involvement with lymphoma. A retrospective chart review was undertaken to identify patients with gut perforation and to determine their clinicopathologic features.
RESULTS: Nine percent (92 of 1062) of patients developed a perforation, of which 55% (51 of 92) occurred after chemotherapy. The median day of perforation after initiation of chemotherapy was 46 days (mean, 83 days; range, 2-298) and 44% of perforations occurred within the first 4 weeks of treatment. Diffuse large B-cell lymphoma (DLBCL) was the most common lymphoma associated with perforation (59%, 55 of 92). Compared with indolent B-cell lymphomas, the risk of perforation was higher with aggressive B-cell lymphomas (hazard ratio, HR = 6.31, P < 0.0001) or T-cell/other types (HR = 12.40, P < 0.0001). The small intestine was the most common site of perforation (59%).
CONCLUSION: Perforation remains a significant complication of GI lymphomas and is more frequently associated with aggressive than indolent lymphomas. Supported in part by University of Iowa/Mayo Clinic SPORE CA97274 and the Predolin Foundation.

PMID 23704194
E T Dryver, H Jernström, K Tompkins, R Buckstein, K R Imrie
Follow-up of patients with Hodgkin's disease following curative treatment: the routine CT scan is of little value.
Br J Cancer. 2003 Aug 4;89(3):482-6. doi: 10.1038/sj.bjc.6601052.
Abstract/Text A total of 10-40% of patients with Hodgkin's disease relapse following initial curative therapy. Intensive follow-up is resource intensive and may identify false relapses. We performed a retrospective review of all patients with Hodgkin's disease treated at our centre between 1990 and 1999 to evaluate the utility of the components of follow-up. A total of 107 patients met the inclusion and exclusion criteria. The median age was 33 years and the median duration of follow-up 38 months. The total number of follow-up visits was 1209 and total number of CT scans 283. There were 109 suspected relapses of which 22 proved to be true relapses. Of the latter, 14 were identified clinically, six radiologically and two via lab testing. The routine CT scan detected only two relapses (9%), yet accounted for 29% of the total follow-up costs. Based on data from our centre, the cost per true relapse was $6000 US, 49% incurred by radiological tests. The majority of the cost of follow-up was incurred by routine follow-up (84%) as opposed to the investigation of suspected relapses (16%). We conclude that most true relapses are clinically symptomatic and that the routine CT is an expensive and inefficient mode of routine follow-up.

PMID 12888816
M Liedtke, P A Hamlin, C H Moskowitz, A D Zelenetz
Surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at time of relapse: a retrospective analysis of a uniformly-treated patient population.
Ann Oncol. 2006 Jun;17(6):909-13. doi: 10.1093/annonc/mdl049. Epub 2006 May 3.
Abstract/Text BACKGROUND: Approximately one-third of the patients with relapsed aggressive non-Hodgkin's lymphoma (NHL) are cured by second-line chemotherapy followed by high-dose consolidation. The age-adjusted international prognostic index determined at the time of relapse (sAAIPI) predicts outcome in relapsed diffuse large B-cell lymphoma, suggesting that the success of salvage therapy could be enhanced by early relapse detection. This study evaluated the role of surveillance imaging in detection of relapsed disease and its impact on outcome of salvage treatment.
PATIENTS AND METHODS: One hundred and eight patients with relapsed aggressive NHL were treated with ICE-based second-line chemotherapy. Relapses were categorized as detected by imaging, examination, or patient-reported symptoms.
RESULTS: Twenty per cent of relapses were detected by routine imaging while 80% were identified by reported symptoms or abnormalities on exam. Patients were 4.1 times (95% CI: 1.7-10.2) more likely to have low risk disease if relapse was diagnosed by routine imaging (group 1) compared with those diagnosed by reported symptoms or physical findings (group 2). Median overall 5-year survival for group 1 versus group 2 was 54% and 43% respectively (P = 0.13).
CONCLUSION: These results suggest that routine surveillance imaging can identify a population of patients with a more favorable outcome based on the sAAIPI.

PMID 16672295
Tarec El-Galaly, Vineet Prakash, Ilse Christiansen, Jakob Madsen, Preben Johansen, Martin Boegsted, Hans-Erik Johnsen, Anne Bukh
Efficacy of routine surveillance with positron emission tomography/computed tomography in aggressive non-Hodgkin lymphoma in complete remission: status in a single center.
Leuk Lymphoma. 2011 Apr;52(4):597-603. doi: 10.3109/10428194.2010.547642. Epub 2011 Feb 14.
Abstract/Text Post-therapy surveillance imaging in patients with lymphoma remains controversial. We report our experience with positron emission tomography/computed tomography (PET/CT) surveillance in patients with aggressive non-Hodgkin lymphoma in first complete remission (CR). The 138 PET/CTs performed in 52 patients revealed four unsuspected relapses. In one patient, relapse was visualized by fluorodeoxyglucose (FDG) accumulation without any significant CT pathology. The specificity and sensitivity of surveillance PET/CT were 89% and 100%, respectively. The predictive values of positive and negative PET/CTs were 21% and 100%, respectively. The cost of half-yearly routine PET/CT surveillance during the first 2 years in CR was $US8552 per patient and accounted for 81% of the total follow-up costs. PET/CT was effective in detecting unexpected relapse and normal PET/CT supported continuous CR. However, the impact of PET/CT was limited by the high number of false-positive results and PET/CT surveillance was costly compared to CT surveillance.

PMID 21314488

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