P Hoskin

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.

Guidelines for preclinical and early phase clinical assessment of novel radiosensitisers.

SUMMARY There is a growing appreciation of the potential value of combining novel molecularly-targeted drugs with radiotherapy or chemoradiotherapy. Such approaches have the potential to improve locoregional disease control and cure rates across a diverse range of tumour types. In this report, we outline a rational framework for developing novel drug–radiation combinations. In doing so, we make recommendations regarding the core preclinical data sets that are required to serve as justification for studies in humans and describe potential clinical trial designs that may be adopted by investigators. Radiotherapy (RT) has a pivotal role in the management of many tumours, such that B50% of cancer patients will receive RT during the course of their illnesses and 40% of those cured of cancer will have received RT as part of their treatment (http://info.cancerresearchuk. org/). Indications for prescribing RT include (i) definitive, curative (radical) treatment; (ii) adjuvant therapy following surgery in an attempt to eradicate microscopic (or rarely macroscopic) residual disease; and (iii) as palliative treatment to ameliorate cancerrelated symptoms. In the majority of situations, RT is a highly localised treatment that targets defined volumes of tissue that are known (or suspected) to contain cancer cells. Wide-field hemibody (Bashir et al, 2008) or total body (Adkins and DiPersio, 2008) irradiation techniques are used rarely in very specific indications, such as metastatic bone disease or ‘conditioning’ before transplantation in haematological malignancies, respectively. In addition, the latest developments in stereotactic body RT (SBRT) techniques have also resulted in protocols that aim to treat oligometastatic disease spread through an organ (or more than

High-dose BEAM chemotherapy with autologous haemopoietic stem cell transplantation for Hodgkin's disease is unlikely to be associated with a major increased risk of secondary MDS/AML.

SummaryHodgkin’s disease is curable in the majority of patients, although a proportion of patients are resistant to or relapse after initial therapy. High-dose therapy with autologous stem cell support has become the standard salvage therapy for patients failing chemotherapy, but there have been reports of a high incidence of myelodysplasia/acute myeloid leukaemia (MDS/AML) following such treatment. Patients who receive such therapy form a selected group, however, who have already been subjected to other leukaemogenic factors, such as treatment with alkylating agents. In order to ascertain the true risk of MDS/AML, comparison must be made with other patients subjected to the same risks but not undergoing transplantation. We report a retrospective comparative study of 4576 patients with Hodgkin’s disease from the BNLI and UCLH Hodgkin’s databases, which includes 595 patients who have received a transplant. Statistical analysis including Cox’s proportional hazards multivariate regression model with time-dependent covariates was employed. This analysis reveals that the risk of developing MDS/AML was dominated by three factors, namely quantity of prior therapy (relative risk [RR] 2.01, 95% confidence intervals [CI] 1.49–2.71, for each treatment block, P < 0.0001) and whether the patient had been exposed to MOPP (RR 3.61, 95% CI 1.64–7.95, P = 0.0009) or lomustine chemotherapy (RR 4.53, 95% CI 1.96–10.44, P = 0.001). Following adjustment for these factors in the multivariate model the relative risk associated with transplantation was 1.83 (95% CI 0.66–5.11, P = 0.25). This study provides no evidence of a significantly increased risk of MDS/AML associated with BEAM therapy and autologous transplantation in Hodgkin’s disease. Concern over MDS/AML should not mitigate against the timely use of this treatment modality.

A phase III trial comparing CHOP to PMitCEBO with or without G-CSF in patients aged 60 plus with aggressive non-Hodgkin's lymphoma.

The management of older patients with aggressive non-Hodgkins lymphoma presents a challenge to the physician. Age is a poor prognostic indicator, due to reduced ability to tolerate and maintain dose-intensive chemotherapy. Generally, older patients demonstrate a lower response rate, reduced survival and increased toxicity, although the majority of large randomised trials exclude older patients. This randomised trial was conducted in patients 60 years or over to compare CHOP (cyclophosphamide 750 mg m−2, doxorubicin 50 mg m−2, vincristine 1.4 mg m−2, prednisolone 100 mg) with PMitCEBO (mitoxantrone 7 mg m−2, cyclophosphamide 300 mg m−2, etoposide 150 mg m−2, vincristine 1.4 mg m−2, bleomycin 10 mg m−2 and prednisolone 50 mg). Due to the myelosuppressive nature of these regimens, patients were also randomised to the addition of G-CSF. The formal results of this trial with long-term follow-up are now reported. Data were analysed to assess efficacy and toxicity. Overall response rate was 84% in the CHOP arm and 83% in the PMitCEBO arm, with overall response rates of 83% for the use of G-CSF and 84% for no G-CSF. At median 44 months follow-up, there was no significant difference in failure-free, progression-free or overall survival between the CHOP and PMitCEBO arms. At 3 years, the actuarial failure-free survival was 44% in CHOP recipients and 42% in PMitCEBO recipients and the 3-year actuarial overall survival was 46% and 45% respectively. There was no significant difference in the failure-free, progression-free or overall survival with the addition of G-CSF.

A randomised comparison of a third-generation regimen (PACEBOM) with a standard regimen (CHOP) in patients with histologically aggressive non-Hodgkin's lymphoma : a British National Lymphoma Investigation report

A combination of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) has been a standard therapy for histologically aggressive non-Hodgkins lymphomas for over 20 years, but several newer regimens, referred to as second or third generation, have been reported to give improved results in single-centre studies. Positive evidence from randomised trials has been lacking, and the British National Lymphoma Investigation therefore commenced a randomised comparison of CHOP vs a third-generation regimen, PACEBOM, in November 1987. A total of 459 eligible patients were entered into the trial: 226 in the CHOP arm and 233 in the PACEBOM arm. Overall, there was no significant difference in outcome between the two arms of the trial. In patients with stage IV disease there was an apparent improvement in survival for those treated with PACEBOM, but considerable caution must be exercised with such subgroup analysis.

Breast cancer risk following Hodgkin lymphoma radiotherapy in relation to menstrual and reproductive factors.

Background:Women treated with supradiaphragmatic radiotherapy (sRT) for Hodgkin lymphoma (HL) at young ages have a substantially increased breast cancer risk. Little is known about how menarcheal and reproductive factors modify this risk.Methods:We examined the effects of menarcheal age, pregnancy, and menopausal age on breast cancer risk following sRT in case–control data from questionnaires completed by 2497 women from a cohort of 5002 treated with sRT for HL at ages <36 during 1956–2003.Results:Two-hundred and sixty women had been diagnosed with breast cancer. Breast cancer risk was significantly increased in patients treated within 6 months of menarche (odds ratio (OR) 5.52, 95% confidence interval (CI) (1.97–15.46)), and increased significantly with proximity of sRT to menarche (Ptrend<0.001). It was greatest when sRT was close to a late menarche, but based on small numbers and needing reexamination elsewhere. Risk was not significantly affected by full-term pregnancies before or after treatment. Risk was significantly reduced by early menopause (OR 0.55, 95% CI (0.35–0.85)), and increased with number of premenopausal years after treatment (Ptrend=0.003).Conclusion:In summary, this paper shows for the first time that sRT close to menarche substantially increases breast cancer risk. Careful consideration should be given to follow-up of these women, and to measures that might reduce their future breast cancer risk.

Long-term follow-up of patients treated with radiotherapy alone for early-stage histologically aggressive non-Hodgkin's lymphoma

Historically localised aggressive non-Hodgkins lymphoma (NHL) has been treated with involved field radiotherapy (RT), chemotherapy, or a combination of both modalities. The current weight of evidence supports a preference for combined modality treatment (CMT). Increased patient age at diagnosis is well recognised as a poor prognostic indicator in NHL, but despite this some perceive CMT as too toxic for use in the elderly. As a result, some older patients continue to be offered RT alone. Here, we present long-term follow-up of 377 adults of all ages treated with RT alone for early-stage diffuse large-cell lymphoma on British National Lymphoma Investigation trials between 1974 and 1997. 10-year cause-specific survival in patients older than 60 years was poor and significantly inferior to that in younger patients (47 and 75% respectively; P<0.001). There is growing evidence that short-course chemotherapy, with or without RT, is superior to RT alone in early-stage aggressive NHL, in elderly as well as in younger patients. Increased age alone should not exclude patients from systemic treatment for early-stage aggressive NHL.

Long Term Outcome in Adolescents with Hodgkin's Lymphoma: Poor Results using Regimens Designed for Adults

It is unclear whether the outcome in adolescents with Hodgkins lymphoma is as good as that in children and there are no prospective randomized trials comparing regimes used in children and adults in this setting. We have therefore performed an analysis of 210 adolescent patients diagnosed with Hodgkins lymphoma between 1970-1997 and registered on the database held by the British National Lymphoma Investigation. Patients were treated according to adult regimens current at the time of their diagnosis. The complete response rate recorded in 209 patients was 76%. This was highly dependent on disease stage being 95% in patients with localized disease but 63% in those with advanced disease. The 5 year event free survival for the whole cohort was 50% falling to 41% at 20 years with overall survival of 81% falling to 68% at 5 and 20 years respectively. There is no significant difference in the 3 decades pertaining to this analysis. Of the 62 deaths in this cohort, 70% were due to Hodgkins lymphoma but of the 13 deaths occurring beyond 10 years, only 3 were due to Hodgkins lymphoma, the reminder being attributable to the late effects of therapy. Results from paediatric groups have been much more encouraging than those presented from this cohort. It seems the use of risk-adjusted combined modality therapy with minimization of radiation fields and doses and reduction of anthracycline and alkylator exposure has been successful in children and should be used in adolescents.