Barry W. Hancock

Risk of Second Malignancy After Hodgkin’s Disease in a Collaborative British Cohort: The Relation to Age at Treatment

PURPOSE To assess long-term site-specific risks of second malignancy after Hodgkins disease in relation to age at treatment and other factors. PATIENTS AND METHODS A cohort of 5,519 British patients with Hodgkins disease treated during 1963 through 1993 was assembled and followed-up for second malignancy and mortality. Follow-up was 97% complete. RESULTS Three hundred twenty-two second malignancies occurred. Relative risks of gastrointestinal, lung, breast, and bone and soft tissue cancers, and of leukemia, increased significantly with younger age at first treatment. Absolute excess risks and cumulative risks of solid cancers and leukemia, however, were greater at older ages than at younger ages. Gastrointestinal cancer risk was greatest after mixed-modality treatment (relative risk [RR] = 3.3; 95% confidence interval [CI], 2.1 to 4.8); lung cancer risks were significantly increased after chemotherapy (RR = 3. 3; 95% CI, 2.4 to 4.7), mixed-modality treatment (RR = 4.3; 95% CI, 2.9 to 6.2), and radiotherapy (RR = 2.9; 95% CI, 1.9 to 4.1); breast cancer risk was increased only after radiotherapy without chemotherapy (RR = 2.5; 95% CI, 1.4 to 4.0); and leukemia risk was significantly increased after chemotherapy (RR = 31.6; 95% CI, 19.7 to 47.6) and mixed-modality treatment (RR = 38.1; 95% CI, 24.6 to 55. 9). These risks were generally greater after treatment at younger ages: for patients treated at ages younger than 25 years, there were RRs of 18.7 (95% CI, 5.8 to 43.5) for gastrointestinal cancer after mixed-modality treatment, 14.4 (95% CI, 5.7 to 29.3) for breast cancer after radiotherapy, and 85.2 (95% CI, 45.3 to 145.7) for leukemia after chemotherapy (with or without radiotherapy). CONCLUSION Age at treatment has a major effect on risk of second malignancy after Hodgkins disease. Although absolute excess risks are greater for older patients, RRs of several important malignancies are much greater for patients who are treated when young. The increased risk of gastrointestinal cancers may relate particularly to mixed-modality treatment, and that of lung cancer to chemotherapy as well as radiotherapy; there are also well-known increased risks of breast cancer from radiotherapy and leukemia from chemotherapy. The roles of specific chemotherapeutic agents in the etiology of solid cancers after Hodgkins disease require detailed investigation.

Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit: a meta-analysis of the randomised trials

BACKGROUND Several randomised trials have compared interferon-alpha with control as adjuvant therapy for high-risk malignant melanoma. The results of the individual trials have been either inconclusive or even apparently conflicting. To assess all the available evidence we performed a meta-analysis of these trials. METHODS Standard methods for quantitative meta-analysis based on published data were used. Endpoints evaluated were recurrence-free survival and overall survival. A subgroup analysis by dose of interferon-alpha was performed. FINDINGS Twelve trials, comprising 14 comparisons of interferon-alpha with control, with results available were identified. Recurrence-free survival was improved with interferon-alpha: hazard ratio 0.83, 95% confidence interval 0.77 to 0.90, p=0.000003. The benefit on overall survival was less clear (0.93, 0.85 to 1.02, p=0.1) and the confidence interval is compatible both with no benefit and with a moderate, but clinically worthwhile, benefit. There was some evidence of a dose response relationship with a significant trend for the benefit of interferon-alpha to increase with increasing dose for recurrence-free survival (test for trend: p=0.02) but not for overall survival (trend: p=0.8). INTERPRETATION This meta-analysis provides the most reliable synthesis of the data currently available. Adjuvant interferon-alpha produces clear reductions in recurrence of high-risk melanoma, with some evidence of an effect of dose of interferon-alpha, but it is unclear whether this translates into a worthwhile survival benefit or not. Additional and more mature data are needed to resolve these issues and an individual patient data meta-analysis should be performed.

Results of a Trial of PET-Directed Therapy for Early-Stage Hodgkin’s Lymphoma

BACKGROUND It is unclear whether patients with early-stage Hodgkins lymphoma and negative findings on positron-emission tomography (PET) after three cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) require radiotherapy. METHODS Patients with newly diagnosed stage IA or stage IIA Hodgkins lymphoma received three cycles of ABVD and then underwent PET scanning. Patients with negative PET findings were randomly assigned to receive involved-field radiotherapy or no further treatment; patients with positive PET findings received a fourth cycle of ABVD and radiotherapy. This trial assessing the noninferiority of no further treatment was designed to exclude a difference in the 3-year progression-free survival rate of 7 or more percentage points from the assumed 95% progression-free survival rate in the radiotherapy group. RESULTS A total of 602 patients (53.3% male; median age, 34 years) were recruited, and 571 patients underwent PET scanning. The PET findings were negative in 426 of these patients (74.6%), 420 of whom were randomly assigned to a study group (209 to the radiotherapy group and 211 to no further therapy). At a median of 60 months of follow-up, there had been 8 instances of disease progression in the radiotherapy group, and 8 patients had died (3 with disease progression, 1 of whom died from Hodgkins lymphoma); there had been 20 instances of disease progression in the group with no further therapy, and 4 patients had died (2 with disease progression and none from Hodgkins lymphoma). In the radiotherapy group, 5 of the deaths occurred in patients who received no radiotherapy. The 3-year progression-free survival rate was 94.6% (95% confidence interval [CI], 91.5 to 97.7) in the radiotherapy group and 90.8% (95% CI, 86.9 to 94.8) in the group that received no further therapy, with an absolute risk difference of -3.8 percentage points (95% CI, -8.8 to 1.3). CONCLUSIONS The results of this study did not show the noninferiority of the strategy of no further treatment after chemotherapy with regard to progression-free survival. Nevertheless, patients in this study with early-stage Hodgkins lymphoma and negative PET findings after three cycles of ABVD had a very good prognosis either with or without consolidation radiotherapy. (Funded by Leukaemia and Lymphoma Research and others; RAPID ClinicalTrials.gov number, NCT00943423.).

Adjuvant Interferon in High-Risk Melanoma: The AIM HIGH Study—United Kingdom Coordinating Committee on Cancer Research Randomized Study of Adjuvant Low-Dose Extended-Duration Interferon Alfa-2a in High-Risk Resected Malignant Melanoma

PURPOSE To evaluate low-dose extended duration interferon alfa-2a as adjuvant therapy in patients with thick (> or = 4 mm) primary cutaneous melanoma and/or locoregional metastases. PATIENTS AND METHODS In this randomized controlled trial involving 674 patients, the effect of interferon alfa-2a (3 megaunits three times per week for 2 years or until recurrence) on overall survival (OS) and recurrence-free survival (RFS) was compared with that of no further treatment in radically resected stage IIB and stage III cutaneous malignant melanoma. RESULTS The OS and RFS rates at 5 years were 44% (SE, 2.6) and 32% (SE, 2.1), respectively. There was no significant difference in OS or RFS between the interferon-treated and control arms (odds ratio [OR], 0.94; 95% CI, 0.75 to 1.18; P =.6; and OR, 0.91; 95% CI, 0.75 to 1.10; P =.3; respectively). Male sex (P =.003) and regional lymph node involvement (P =.0009), but not age (P =.7), were statistically significant adverse features for OS. Subgroup analysis by disease stage, age, and sex did not show any clear differences between interferon-treated and control groups in either OS or RFS. Interferon-related toxicities were modest: grade 3 (and in only one case, grade 4) fatigue or mood disturbance was seen in 7% and 4% respectively, of patients. However, there were 50 withdrawals (15%) from interferon treatment due to toxicity. CONCLUSION The results from this study, taken in isolation, do not indicate that extended-duration low-dose interferon is significantly better than observation alone in the initial treatment of completely resected high-risk malignant melanoma.

Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients.

PURPOSE In patients with stage IV melanoma, durable responses have been reported with treatment regimens that involve high-dose interleukin-2 (IL-2). We analyze long-term results of 631 melanoma patients from 12 institutions who had received IL-2 alone, in combination with interferon alfa 2a or 2b (IFNalpha), or with cytotoxic drugs. METHODS Case records that contained pretreatment parameters, response data, and updated survival information were collected. After univariate analysis, the multivariate evaluation of the impact of pretreatment parameters on response and survival was performed by logistic regression and Coxs regression, respectively. RESULTS Patients were divided into four groups according to treatment: IL-2 alone (n=117), IL-2 and chemotherapy (n=49), IL-2 and IFNalpha (n=153), and IL-2, chemotherapy, and IFNalpha (n=312). The median survival of all patients was 10.5 months and the 2- and 5-year survival rates were 19.9% and 10.4%, respectively. Independent prognostic factors for response and survival were entirely different, treatment group being the only significant factor for response, and serum lactate dehydrogenase (LDH), metastatic site, and performance predicting survival. The addition of IFNalpha to IL-2 was associated with prolonged survival, but the effect of additional chemotherapy was less obvious. CONCLUSION Serum LDH, metastatic site, and performance status are useful stratification factors for randomized trials in metastatic melanoma. The improved long-term survival rates observed in melanoma patients treated with IL-2/IFNalpha-containing regimens are notable in contrast to the reported 5-year survival rates of 2% to 6% achieved with chemotherapy, but because selection bias cannot be ruled out, the impact of IL-2, as well as all other components of the treatment regimens, on survival needs to be confirmed in prospective randomized trials.

Randomized Comparison of the Stanford V Regimen and ABVD in the Treatment of Advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244

PURPOSE This multicenter, prospective, randomized controlled trial compared the efficacy and toxicity of two chemotherapy regimens in advanced Hodgkins lymphoma (HL): the weekly alternating Stanford V and the standard, twice-weekly regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). PATIENTS AND METHODS Patients had stage IIB, III, or IV disease or had stages I to IIA disease with bulky disease or other adverse features. Radiotherapy was administered in both arms to sites of previous bulk (> 5 cm) and to splenic deposits, although this was omitted in the latter part of the trial for patients achieving complete remission (CR) in the ABVD arm. A total of 520 patients were randomly assigned and were assessed for the primary outcome measure of progression-free survival (PFS). Five hundred patients received protocol treatment, and radiotherapy was administered to 73% in the Stanford V arm and to 53% in the ABVD arm. RESULTS The overall response rates after completion of all treatment were 91% for Stanford V and 92% for ABVD. During a median follow-up of 4.3 years, there was no evidence of a difference in projected 5-year PFS and overall survival (OS) rates (76% and 90%, respectively, for ABVD; 74% and 92%, respectively, for Stanford V). More pulmonary toxicity was reported for ABVD, whereas other toxicities were more frequent with Stanford V. CONCLUSION In a large, randomized trial, the efficacies of Stanford V and ABVD were comparable when given in combination with appropriate radiotherapy.

Risk of Second Malignancy After Non-Hodgkin's Lymphoma: A British Cohort Study

PURPOSE To assess long-term site-specific risks of second malignancy following non-Hodgkins lymphoma (NHL) in relation to treatment and demographic factors. PATIENTS AND METHODS A cohort of 2,456 patients with NHL who were first treated from 1973 to 2000 and were younger than 60 years from centers in the British National Lymphoma Investigation were observed, and occurrences of second malignancy was compared with expectations based on general population cancer rates in England and Wales. RESULTS In total, 123 second malignancies occurred. Relative risks (RRs) were significantly elevated for all malignancies combined (RR = 1.3; 95% CI, 1.1 to 1.6) and for leukemia (RR = 8.8; 95% CI, 5.1 to 14.1) and lung cancer (RR = 1.6; 95% CI, 1.1 to 2.3). RRs of malignancy overall diminished significantly with increasing age at first treatment. Leukemia risk was significantly increased after chemotherapy (RR = 10.5; 95% CI, 5.0 to 19.3) and mixed-modality treatment (RR = 13.0; 95% CI, 5.2 to 26.7). Relative risks of lung (RR = 1.9; 95% CI, 1.1 to 3.1) and colorectal (RR = 2.1; 95% CI, 1.1 to 3.6) cancers were significantly raised following chemotherapy. CONCLUSION NHL patients are at elevated risk of developing second malignancy, particularly leukemia and lung cancer. The relative risk is greater with patients who are younger at first treatment. Chemotherapy predisposes patients toan increased risk of leukemia, and possibly lung and colorectal cancers. The role of specific drug treatments in the etiology of solid cancers after NHL deserves further investigation.

A UK multicentre phase II study of rituximab (chimaeric anti‐CD20 monoclonal antibody) in patients with follicular lymphoma, with PCR monitoring of molecular response

Follicular lymphoma (FL) cells express CD20 and are associated in most cases with the t(14;18) chromosomal translocation. A multicentre study was undertaken between January 1997 and January 1998 to assess the complete response rate (CR) and overall response rate (RR) to rituximab, a chimaeric anti‐CD20 monoclonal antibody. Seventy patients with previously treated FL received rituximab (375 mg/m2/week ×4, by intravenous infusion). Restaging studies were performed 1 and 2 months after therapy. Molecular monitoring for the presence of cells harbouring the Bcl‐2/JH gene rearrangement in the peripheral blood (PB) and bone marrow (BM) was performed before and after treatment using a two‐step semi‐nested polymerase chain reaction (PCR) assay. The overall RR was 32/70 (46%), being highest in patients who had received only one previous treatment (12/15, 80%). However, only two patients achieved a CR. The median duration of response was 11 months. Thirteen of 21 evaluable ‘PCR‐positive’ patients (62%) became ‘PCR‐negative’ in PB and/or BM samples 1 month after rituximab, although this did not correlate with clinical response. Treatment was generally well tolerated, although one patient developed Stevens–Johnson syndrome. Rituximab was shown to be active in FL, and in some cases PB and/or BM became PCR negative. Studies in combination with cytotoxic chemotherapy to increase the CR rate are warranted.

Comparison of ABVD and Alternating or Hybrid Multidrug Regimens for the Treatment of Advanced Hodgkin's Lymphoma: Results of the United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519)

PURPOSE To perform an open-label, randomized, controlled trial comparing treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with two multidrug regimens (MDRs) for advanced Hodgkins lymphoma (HL). PATIENTS AND METHODS Eight hundred seven patients with advanced HL (stage III to IV, or earlier stage with systemic symptoms or bulky disease) were randomly assigned between ABVD and MDR specified before randomization as alternating chlorambucil, vinblastine, procarbazine, and prednisolone (ChlVPP) with prednisolone, doxorubicin, bleomycin, vincristine, and etoposide (PABIOE), or hybrid ChlVPP/etoposide, vincristine, and doxorubicin (EVA). Radiotherapy was planned for incomplete response or initial bulk disease. RESULTS At 52 months median follow-up, 212 event-free survival (EFS) events (disease progression or any death) were reported. In the primary comparison, at 3 years EFS was 75% (95% CI, 71% to 79%) for ABVD and 75% (95% CI, 70% to 79%) for MDRs (hazard ratio [HR] = 1.05; 95% CI, 0.8 to 1.37; HR more than 1.0 favors ABVD). The 3-year overall survival (OS) rates were 90% (95% CI, 87% to 93%) in patients allocated ABVD and 88% (95% CI, 84% to 91%) in patients allocated MDRs (HR = 1.22; 95% CI, 0.84 to 1.77). Patients receiving MDRs experienced more grade 3/4 infection, mucositis, and neuropathy. One occurrence of myelodysplastic syndrome was reported, but no acute leukemia was reported. When the two MDRs are compared separately with ABVD, neither the alternating nor the hybrid regimen showed a statistically significant difference from ABVD for EFS or OS. Subgroup analysis suggested that MDRs may be associated with poorer outcomes in older patients (heterogeneity test of OS older or younger than 45 years, P = .020). CONCLUSION There was no evidence of significant difference in EFS or OS between ABVD and MDRs in the trial overall or if the two MDR versus ABVD comparisons are considered separately. ABVD remains the standard for treatment of advanced HL.

Second Cancer Risk After Chemotherapy for Hodgkin's Lymphoma: A Collaborative British Cohort Study

PURPOSE We investigated the long-term risk of second primary malignancy after chemotherapy for Hodgkins lymphoma (HL) in a much larger cohort than any yet published, to our knowledge. PATIENTS AND METHODS We followed 5,798 patients with HL treated with chemotherapy in Britain from 1963 to 2001--of whom 3,432 also received radiotherapy--to assess second primary malignancy risks compared with general population-based expectations. RESULTS Second malignancies occurred in 459 cohort members. Relative risk (RR) of second cancer was raised after chemotherapy alone (RR, 2.0; 95% CI, 1.7 to 2.4) but was much lower than after combined modalities (RR, 3.9; 95% CI, 3.5 to 4.4). After chemotherapy alone, there were significantly raised risks of lung cancer, non-HL, and leukemia, each contributing approximately equal absolute excess risk. After combined modalities, there were raised risks of these and several other cancers. Second cancer risk peaked 5 to 9 years after chemotherapy alone, but it remained raised for 25 years and longer after combined modalities. Risk was raised after each common chemotherapy regimen except, based on limited numbers and follow-up, adriamycin, bleomycin, vinblastine, and dacarbazine. The age and time-course relations of lung cancer differed between chemotherapy alone and combined modalities. CONCLUSION Although chemotherapy alone leads to raised risk of second malignancy, this risk is lower and affects fewer anatomic sites than that after combined modalities, and it is slight if at all after 15 years follow-up. The mechanism of lung cancer etiology may differ between chemotherapy and radiotherapy.