Chemotherapy, radiotherapy and combined modality for Hodgkin's disease, with emphasis on second cancer risk

Abstract

Second malignancies (SM) are a major late effect of treatment for Hodgkin's disease (HD). Reliable comparisons of SM risk between alternative treatment strategies are lacking. Radiotherapy (RT), chemotherapy (CT) and combined chemo‐radiotherapy (CRT) for newly‐diagnosed Hodgkin's disease are compared with respect to SM risk, overall (OS) and progression‐free (PFS) survival. Further, involved‐field (IF‐)RT is compared to extended‐field (EF‐)RT. We searched the Cochrane Controlled Trials Register, PubMed, EMBASE, CancerLit, LILACS, relevant conference proceedings, trials lists and publications. RCTs accruing 30+ patients and completing accrual before/during 2000, comparing at least two treatment modalities for newly‐diagnosed HD. Individual patient data were collected and assessed for data quality. Trialists submitted additional information concerning methods and data quality. Peto Odds Ratios (OR) with 95% confidence intervals (CI) were calculated for OS, PFS and SM‐free survival. Secondary acute leukaemia (AL), non‐Hodgkin's lymphoma (NHL) and solid tumours (ST) were also analysed separately. 37 trials (9312 patients) were analysed: 15 (3343) for RT vs. CRT, 16 (2861) for CT vs. CRT, 3 (415) for RT vs. CT and 10 (3221) for IF‐RT vs. EF‐RT. CRT was superior to RT in terms of OS (OR=0.76, 95% CI 0.66 to 0.89, P = 0.0004), PFS (OR=0.49, 95% CI 0.43 to 0.56, P < 0.0001) and SM (OR = 0.78, 95% CI 0.62 to 0.98, P = 0.03). The superiority of CRT also applied to early and advanced stages (mainly IIIA) separately. Excess SM with RT is due mainly to ST and is apparently caused by greater need for salvage therapy after RT. CRT was superior to CT in terms of PFS (OR = 77, 95 % CI 0.68 to 0.77, P < 0.0001). OS was better with CRT for early stages only (OR=0.62, 95% CI 0.44 to 0.88, P = 0.006). SM risk was higher with CRT (OR = 1.38, 95% CI 1.00 to 1.89, P = 0.05), although not significant for early stages alone. This effect, also seen in AL and ST separately, was due directly to first‐line treatment. Data were insufficient to compare RT to CT. EF‐RT was superior to IF‐RT (each additional to CT in most trials) in terms of PFS (OR=81, 95% CI 0.68 to 0.95, P = 0.009) but not OS. No significant difference in SM was observed. CRT seems to be optimal for most early stage (I‐II) HD patients. For advanced stages (III to IV), CRT better prevents progression/relapse but CT alone seems to cause less SM. RT alone gives a higher overall SM risk than CRT due to increased need for salvage therapy. Reduced SM risk after IF‐RT instead of EF‐RT could not be demonstrated. Due to the large number of studies excluded because no IPD were received, to the inclusion of many outdated treatments and to the limited amount of long‐term data, one must be cautious in applying these results to current therapies. 何杰金氏疾病的化學治療,放射線治療及合併療法造成次發性惡性疾病的風險 次發性惡性疾病是何杰金氏疾病治療的主要後遺症。目前對於不同治療方式造成次發性惡性疾病的風險仍缺乏可信的比較。 比較新診斷的何杰金氏疾病接受放射線治療,化學治療及合併化放療發生次發性惡性疾病的風險,整體存活(OS)及無病存活(PFS)率。另外也進一步比較腫瘤侵犯部位(IF)放射治療和廣泛範圍(EF)放射治療的差異。 我們搜尋考科藍圖書館, PubMed, EMBASE, Cancer Lit, LILACS,可信的會議紀錄、臨床試驗及發表文獻 曾在2000年當年和之前完成進案至少三十個病人的隨機控制試驗，且比較至少兩種新診斷的何杰金氏疾病治療方法。 收集並評估個別病人資料的品質。臨床試驗者登入需加入關於方法及數據品質的資訊，計算整體存活率(OS)、 無病存活(PFS)及無次發性惡性疾病生存(SMfree)率在95%信賴區間的風險比(OR)。同時也個別分析次發性的急性白血病、非何杰金氏淋巴瘤及惡性腫瘤的風險。 共分析37個臨床試驗(包含9312病人)：15個試驗(3343人)比較放射治療和合併化放療。16個臨床試驗(2861人)比較化學治療和合併化放療，3個試驗(415人)比較放射治療和化學治療，10個試驗(3221人)比較腫瘤侵犯部位放射治療或廣泛範圍放射治療。合併化放療在整體存活率(OR = 0.76, CI = 0.66 to 0.89, p = 0.0004),無病存活(OR = 0.49, CI = 0.43 to 0.56, p<0.0001)，次發性惡性疾病(OR = 0.78. CI = 0.62 to 0.98, p = 0.03) 等都優於放射治療。合併化放療分別在早期或是晚期(主要是IIIA期)的病人都有較優異的成績。放射治療後造成過多的次發性惡性疾病主要是因為實質固態腫瘤以及在放射治療後需要更多的援救治療。合併化放療的無病存活率優於化學治療(OR = 77, CI 0.68 to 0.77, p<0.0001) 。只有早期病患接受合併化放療才會有較好的整體存活率(OR = 0.62, CI 0.44 to 0.88, p = 0.006)。次發性惡性疾病的危險性在合併化放療較高(OR = 1.38, CI 1.00 to 1.89, p = 0.05),但在早期病患並沒有顯著意義。這樣的效果可能因為使用第一線治療,其效果在急性白血病及實質固態瘤同時可見。目前比較放射治療和化學治療的數據是不充足的。廣泛範圍放射治療的無病存活率(PFS)優於腫瘤侵犯範圍放射治療(大多數試驗都搭配化學治療)(OR = 81, CI 0.68 to 0.95, p = 0.009),但是在整體存活率是沒有差別。對於次發性惡性疾病並無顯著的差異。...