A case study evaluating deep inspiration breath-hold and intensity-modulated radiotherapy to minimise long-term toxicity in a young patient with bulky mediastinal Hodgkin lymphoma.

Radiotherapy plays an important role in the treatment of early-stage Hodgkin lymphoma, but late toxicities such as cardiovascular disease and second malignancy are a major concern. Our aim was to evaluate the potential of deep inspiration breath-hold (DIBH) and intensity-modulated radiotherapy (IMRT) to reduce cardiac dose from mediastinal radiotherapy. A 24 year-old male with early-stage bulky mediastinal Hodgkin lymphoma received involved-site radiotherapy as part of a combined modality programme. Simulation was performed in free breathing (FB) and DIBH. The target and organs at risk were contoured on both datasets. Free breathing-3D conformal (FB-3DCRT), DIBH-3DCRT, FB-IMRT and DIBH-IMRT were compared with respect to target coverage and doses to organs at risk. A 'butterfly' IMRT technique was used to minimise the low-dose bath. In our patient, both DIBH (regardless of mode of delivery) and IMRT (in both FB and DIBH) achieved reductions in mean heart dose. DIBH improved all lung parameters. IMRT reduced high dose (V20), but increased low dose (V5) to lung. DIBH-IMRT was chosen for treatment delivery. Advanced radiotherapy techniques have the potential to further optimise the therapeutic ratio in patients with mediastinal lymphoma. Benefits should be assessed on an individualised basis.

Impact of advancing age on treatment and outcomes in anal cancer.

BACKGROUND: Chemoradiotherapy (CRT) for squamous cell carcinoma of the anus (SCCA) may cause significant toxicity, and concerns exist about its tolerability in the elderly. The authors compared tolerability and outcomes across the age groups following CRT for SCCA. METHODS: Single-institution retrospective analysis of patients with localized SCCA treated with CRT. CRT was standardized at 50.4-54 Gy, with concurrent infusional 5-fluorouracil and mitomycin C. Patients were arbitrarily categorized into three groups: Group 1 - age < 50 years; Group 2 - age ≥ 50 and < 70 years; and Group 3 - age ≥ 70 years. RESULTS: Of 284 patients identified, 278 were evaluable. The number of patients in each age group was: Group 1 - 51; Group 2 - 140; and Group 3 - 93. Baseline and treatment characteristics, tumor stage, rates of overall acute toxicity, need for unplanned treatment breaks and chemotherapy delivery were largely similar across the age groups. However, nine patients in Group 3 did not complete CRT, compared with five and none in Groups 1 and 2, respectively (p = 0.006). In addition, five patients in Group 3 had diarrhea requiring treatment break, compared with none in the other two groups (p = 0.004). At a median follow-up 5.3 years, there was no significant difference in overall survival (p = 0.11), disease-free survival (p = 0.22) or local-recurrence free survival (p = 0.34), across the three age groups. CONCLUSIONS: CRT is safe and tolerable in the elderly age group, and provides equivalent disease control rates compared with the younger age group. Age alone should therefore not preclude aggressive curative treatment.

Aggressive behavior of cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia.

OBJECTIVES/HYPOTHESIS: Immunosuppression in organ transplant recipients increases the incidence and aggressiveness of cutaneous squamous cell carcinoma. However, there are little clinical data on cutaneous squamous cell carcinoma in patients with immunosuppression due to chronic lymphocytic leukemia. In this study we evaluated the clinical features, patterns of recurrence, and outcomes of cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia. STUDY DESIGN: Retrospective cohort study. METHODS: A review was performed of 42 consecutive patients with cutaneous squamous cell carcinoma and chronic lymphocytic leukemia presenting to our institution between July 2000 and July 2010. Baseline characteristics, treatment details, and outcomes were analyzed. RESULTS: Thirty-four patients presented with primary cutaneous squamous cell carcinoma (33 node negative, 1 node positive), and eight patients presented with nodal disease without a simultaneous index primary. The 2-year cumulative incidence of local recurrence for primary cutaneous squamous cell carcinoma was 15%. Nodal recurrence occurred in 36% of node-negative patients. The 3-year overall and cause-specific survival rate for all patients was 37% and 65%, respectively. In patients managed curatively for nodal disease at presentation or relapse (n = 17), the 3-year overall and cause-specific survival rate was 21% and 53%, respectively. CONCLUSIONS: Patients with cutaneous squamous cell carcinoma and chronic lymphocytic leukemia experience higher rates of skin cancer recurrence and death than expected in an immunocompetent population. Novel strategies are needed to improve outcomes.

Utility of positron emission tomography/computed tomography for nodal staging of cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia.

PURPOSE: Cutaneous squamous cell carcinoma (cSCC) behaves aggressively in patients with chronic lymphocytic leukemia (CLL). Lymphadenopathy due to CLL can obscure the clinical and radiological assessment of nodal involvement by cSCC. This study aimed to evaluate whether functional imaging with positron emission tomography (PET)/computed tomography (CT) may clarify the clinical picture. METHODS: Five consecutive patients with cSCC and CLL who had a PET/CT scan for the purposes of cSCC staging between July 2000 and July 2010 were analyzed. PET/CT findings were compared to histopathology from subsequent neck dissection. RESULTS: PET/CT can distinguish nodal cSCC from leukemic infiltration with high specificity, allowing prompt appropriate management of nodal disease. CONCLUSIONS: PET/CT is a promising modality for nodal staging in patients with cSCC and CLL, with the potential to improve outcomes in this poor prognosis group. Larger confirmatory studies are needed.

Twenty-five-year experience with radical chemoradiation for anal cancer.

PURPOSE: To evaluate the prognostic factors, patterns of failure, and late toxicity in patients treated with chemoradiation (CRT) for anal cancer. METHODS AND MATERIALS: Consecutive patients with nonmetastatic squamous cell carcinoma of the anus treated by CRT with curative intent between February 1983 and March 2008 were identified through the institutional database. Chart review and telephone follow-up were undertaken to collect demographic data and outcome. RESULTS: Two hundred eighty-four patients (34% male; median age 62 years) were identified. The stages at diagnosis were 23% Stage I, 48% Stage II, 10% Stage IIIA, and 18% Stage IIIB. The median radiotherapy dose to the primary site was 54 Gy. A complete clinical response to CRT was achieved in 89% of patients. With a median follow-up time of 5.3 years, the 5-year rates of locoregional control, distant control, colostomy-free survival, and overall survival were 83% (95% confidence interval [CI] 78-88), 92% (95% CI, 89-96), 73% (95% CI, 68-79), and 82% (95% CI, 77-87), respectively. Higher T stage and male sex predicted for locoregional failure, and higher N stage predicted for distant metastases. Locoregional failure occurred most commonly at the primary site. Omission of elective inguinal irradiation resulted in inguinal failure rates of 1.9% and 12.5% in T1N0 and T2N0 patients, respectively. Pelvic nodal failures were very uncommon. Late vaginal and bone toxicity was observed in addition to gastrointestinal toxicity. CONCLUSIONS: CRT is a highly effective approach in anal cancer. However, subgroups of patients fare relatively poorly, and novel approaches are needed. Elective inguinal irradiation can be safely omitted only in patients with Stage I disease. Vaginal toxicity and insufficiency fractures of the hip and pelvis are important late effects that require prospective evaluation.

Can corruption of chromosome cohesion create a conduit to cancer?

Cohesin is a conserved multisubunit protein complex with diverse cellular roles, making key contributions to the coordination of chromosome segregation, the DNA damage response and chromatin regulation by epigenetic mechanisms. Much has been learned in recent years about the roles of cohesin in a physiological context, whereas its potential and emerging role in tumour initiation and/or progression has received relatively little attention. In this Opinion article we examine how cohesin deregulation could contribute to cancer development on the basis of its physiological roles.

Enhanced RAD21 cohesin expression confers poor prognosis and resistance to chemotherapy in high grade luminal, basal and HER2 breast cancers.

INTRODUCTION: RAD21 is a component of the cohesin complex, which is essential for chromosome segregation and error-free DNA repair. We assessed its prognostic and predictive power in a cohort of in situ and invasive breast cancers, and its effect on chemosensitivity in vitro. METHODS: RAD21 immunohistochemistry was performed on 345 invasive and 60 pure in situ carcinomas. Integrated genomic and transcriptomic analyses were performed on a further 48 grade 3 invasive cancers. Chemosensitivity was assessed in breast cancer cell lines with an engineered spectrum of RAD21 expression. RESULTS: RAD21 expression correlated with early relapse in all patients (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.06 to 2.86, P = 0.029). This was due to the effect of grade 3 tumors (but not grade 1 or 2) in which RAD21 expression correlated with early relapse in luminal (P = 0.040), basal (P = 0.018) and HER2 (P = 0.039) groups. In patients treated with chemotherapy, RAD21 expression was associated with shorter overall survival (P = 0.020). RAD21 mRNA expression correlated with DNA copy number, with amplification present in 32% (7/22) of luminal, 31% (4/13) of basal and 22% (2/9) of HER2 grade 3 cancers. Variations in RAD21 mRNA expression in the clinical samples were reflected in the gene expression data from 36 breast cancer cell lines. Knockdown of RAD21 in the MDA-MB-231 breast cancer cell line significantly enhanced sensitivity to cyclophosphamide, 5-fluorouracil and etoposide. The findings for the former two drugs recapitulated the clinical findings. CONCLUSIONS: RAD21 expression confers poor prognosis and resistance to chemotherapy in high grade luminal, basal and HER2 breast cancers. RAD21 may be a novel therapeutic target.

Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice.

Approximately half of cancer-affected patients receive radiotherapy (RT). The doses delivered have been determined upon empirical experience based upon average radiation responses. Ideally higher curative radiation doses might be employed in patients with genuinely normal radiation responses and importantly radiation hypersensitive patients would be spared the consequences of excessive tissue damage if they were identified before treatment. Rad21 is an integral subunit of the cohesin complex, which regulates chromosome segregation and DNA damage responses in eukaryotes. We show here, by targeted inactivation of this key cohesin component in mice, that Rad21 is a DNA-damage response gene that markedly affects animal and cell survival. Biallelic deletion of Rad21 results in early embryonic death. Rad21 heterozygous mutant cells are defective in homologous recombination (HR)-mediated gene targeting and sister chromatid exchanges. Rad21+/- animals exhibited sensitivity considerably greater than control littermates when challenged with whole body irradiation (WBI). Importantly, Rad21+/- animals are significantly more sensitive to WBI than Atm heterozygous mutant mice. Since supralethal WBI of mammals most typically leads to death via damage to the gastrointestinal tract (GIT) or the haematopoietic system, we determined the functional status of these organs in the irradiated animals. We found evidence for GIT hypersensitivity of the Rad21 mutants and impaired bone marrow stem cell clonogenic regeneration. These data indicate that Rad21 gene dosage is critical for the ionising radiation (IR) response. Rad21 mutant mice thus represent a new mammalian model for understanding the molecular basis of irradiation effects on normal tissues and have important implications in the understanding of acute radiation toxicity in normal tissues.