Preoperative downstaging chemoradiation with concurrent irinotecan and capecitabine in MRI-defined locally advanced rectal cancer: a phase I trial (NWCOG-2).

BACKGROUND: The aim of this study was to investigate the safety of neoadjuvant chemoradiation using radiotherapy (RT) combined with concurrent capecitabine and irinotecan for locally advanced rectal cancer before surgery. METHODS: Forty-six patients were recruited and treated on the basis that MRI scanning had shown poor-risk tumours with threatening (< or =1 mm) or involvement of the mesorectal fascia. Conformal RT was given using 3 or 4 fields at daily fractions of 1.8 Gy on 5 days per week to a total dose of 45 Gy. Concurrently oral capecitabine was given twice daily throughout radiotherapy continuously from days 1 to 35 and intravenous irinotecan was given once per week during weeks 1 to 4 of RT. Dose levels were gradually escalated as follows. Dose level 1: capecitabine 650 mg m(-2) b.i.d. and irinotecan 50 mg m(-2); Dose level 2: capecitabine 650 mg m(-2) b.i.d. and irinotecan 60 mg m(-2); Dose level 3: capecitabine 825 mg m(-2) b.i.d. and irinotecan 60 mg m(2); Dose level 4: capecitabine 825 mg m(-2) b.i.d. and irinotecan 70 mg m(-2). RESULTS: Diarrhoea (grade 3, no grade 4) was the main serious acute toxicity with lesser degrees of fatigue, neutropenia, anorexia and palmar-plantar erythrodysesthesia. The recommended dose for future study was dose level 2 at which 3 of 14 patients (21%) developed grade 3 diarrhoea. Postoperative complications included seven pelvic or wound infections and two anastomotic and two perineal wound dehiscences. There were no deaths in the first 30 days postoperatively. Of 41 resected specimens, 11 (27%) showed a pathological complete response (pCR) and five (12%) showed an involved circumferential resection margin (defined as < or =1 mm). The 3-year disease-free survival (intent-to-treat) was 53.2%. CONCLUSION: In patients with poor-risk MRI-defined locally advanced rectal cancer threatening or involving the mesorectal fascia, preoperative chemoradiation based on RT at 45 Gy in 25 daily fractions over 5 weeks with continuous daily oral capecitabine at 650 mg m(-2) b.i.d. days 1-35 and weekly IV irinotecan at 60 mg m(-2) weeks 1-4, provides acceptable acute toxicity and postoperative morbidity with encouraging response and curative resection rates.

Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy.

BACKGROUND: Epigenetic silencing of O(6)-methylguanine-DNA-methyltransferase (MGMT) by promoter methylation is associated with improved survival in glioblastomas treated with alkylating agents. In this study, we investigated MGMT promoter methylation in glioblastomas treated with temozolomide and radiotherapy in a single UK treatment centre. METHODS: Quantitative methylation data at individual CpG sites were obtained by pyrosequencing for 109 glioblastomas. RESULTS: Median overall survival (OS) was 12.4 months with 2-year survival of 17.9%. Pyrosequencing data were reproducible with archival samples yielding data for all glioblastomas. Variation in methylation patterns of discrete CpG sites and intratumoral methylation heterogeneity were observed. A total of 58 out of 109 glioblastomas showed average methylation >non-neoplastic brain in at least one clinical sample; 86% had homogeneous methylation status in multiple samples. Methylation was an independent prognostic factor associated with prolonged progression-free survival (PFS) and OS. Cases with methylation more than 35% had the longest survival (median PFS 19.2; OS 26.2 months, 2-year survival of 59.7%). Significant differences in PFS were seen between those with intermediate or high methylation and unmethylated cases, whereas cases with low, intermediate or high methylation all showed significantly different OS. CONCLUSIONS: These data indicate that MGMT methylation is prognostically significant in glioblastomas given chemoradiotherapy in the routine clinic; furthermore, the extent of methylation may be used to provide additional prognostic stratification.

Locoregional first recurrence after mastectomy: prospective cohort studies with and without immediate chemotherapy.

PURPOSE: To evaluate prospectively the impact of combination chemotherapy in the combined modality treatment of isolated first locoregional recurrence (LRR) following mastectomy for breast cancer. METHODS AND MATERIALS: Between 1979 and 1989, 120 chemotherapy-naive women with isolated LRR as first failure after mastectomy were prospectively identified, uniformly staged, and systematically followed. Treatment consisted of excision if feasible, radical locoregional radiotherapy, and a hormonal maneuver (unless estrogen receptor negative). The initial chemotherapy cohort also received 8 cycles of doxorubicin and cyclophosphamide. This was compared to a subsequent control cohort. RESULTS: For all patients, the 10-year actuarial relapse-free survival +/- 95% confidence interval was 42.1+/-9.2%, and overall survival was 56.8+/-9.1%. No difference was seen in locoregional control between cohorts. At 5 years, distant recurrence-free survival for chemotherapy and control cohort respectively was 75.4+/-10.8% and 60.7+/-12.5% (p = 0.33) and overall survival was 81.9%+/-9.6 and 74.3%+/-11.2 (p = 0.24). Univariate analysis showed no prognostic importance for any imbalance between cohorts. Cox modeling confirmed that complete resection was strongly associated with fewer LRR (hazard ratio [HR] 0.32, p = 0.001) and also with better overall survival (HR 1.82, p = 0.019). Chemotherapy produced a substantial reduction in risk of death (HR 0.72 CI 0.421-1.235, p = 0.23). CONCLUSIONS: In this prospective but nonrandomized study of treatment for first LRR, the risk of death in the later control cohort was 1.39 times the risk in the chemotherapy cohort but failed to reach statistical significance. The results justify further study.

Primary radiotherapy for subglottic carcinoma.

Between 1976 and 1990, 23 patients with subglottic carcinoma of the larynx were treated by one radiotherapist; these were reviewed. Primary radiotherapy was given using small parallel opposed wedged fields to the neck. No mediastinal radiotherapy was used. Mean follow up was 67 (9-165) months. Actuarial analysis showed a 2-year overall survival of 69.0% (78.3% excluding intercurrent deaths), and a 2-year disease free survival of 68.6%. Failure was due to persistent disease (5 patients) or recurrence (2 patients, both with disease T3, salvaged by surgery at 5 and 20 months). No patient developed clinical mediastinal relapse. These better than expected results support the use of primary radiotherapy to the neck alone avoiding conventional mediastinal radiotherapy. A national questionnaire sent to 67 consultant otolaryngologists sought information on perceived incidence, cure rate, and preferred mode of treatment and produced a 67% response rate. The results confirmed our belief that surgeons have a pessimistic perception of the value of radiotherapy in this condition.

The treatment of squamous cell carcinoma of the paranasal sinuses.

Of 72 cases of paranasal sinus malignancy that were identified, 47 were biopsy proven squamous cell carcinomas. Actuarial analysis of these patients receiving both radical and palliative treatment revealed an overall 5-year survival of 37.4%, and a relapse-free survival of 31.6%. For patients receiving radical treatments (i.e. radiotherapy alone, or preoperative radiotherapy followed by elective surgery), the 5-year survival results were identical (46%). In this series radiotherapy alone is an effective treatment, and subsequent planned surgery did not improve the survival.

Stage I endometrial carcinoma: the role of neoadjuvant progesterone therapy.

A prospective study was devised in 1980 to assess the effect on survival of neoadjuvant Provera as part of the primary treatment of endometrial carcinoma in conjunction with surgery and radiotherapy. Between June 1980 and June 1985, 218 patients with Stage I adenocarcinoma of the corpus uteri were allocated on the basis of hospital of presentation to receive either neoadjuvant treatment with medroxyprogesterone acetate (MPA) 100 mg t.i.d. p.o. from diagnosis for 90 days, or no adjuvant treatment (the control group). The minimum follow-up was 5 years. There was no significant difference between the overall actuarial survival in the treatment group (123 cases) and that in the control group (95 cases). This was 83.7% and 69.2% at 5 and 10 years respectively in the treatment group and 78.9% and 70.7% in the control group (P > 0.1).

OC125 immunoscintigraphy in ovarian carcinoma: a comparison with alternative methods of assessment.

The membrane bound, tumour associated antigen CA125 is recognized by the monoclonal antibody OC125 and may be detected in tumour tissue and serum in over 80% of patients with epithelial ovarian carcinomas. A total of 13 immunoscintigrams using 111 MBq 131I-OC125 have been performed in 11 patients. The results have been compared with clinical examination, CT and ultrasound scans, surgical findings and serum CA125 concentrations. Macroscopic disease was present at the time of scanning in 11 patients (less than 2 cm, eight patients, greater than 2 cm, three patients). Clinical examination and ultrasound were positive in three, CT scanning in four, immunoscintography in seven and serum CA125 in eight patients. This pilot study suggest that serum CA125 estimation is the most sensitive indicator of disease activity. However, immunoscintigraphy using this agent may localize residual disease when clinical examination and other radiological investigations fail.

The concepts, diagnosis and management of early imaging changes after therapy for glioblastomas.

Since postoperative radiotherapy plus concomitant temozolomide followed by adjuvant temozolomide has become standard treatment for glioblastoma, the phenomenon of early post-treatment enlargement of the imaged tumour volume, usually without clinical deterioration, has become widely recognised. The term pseudoprogression has been used to describe a poorly understood pathophysiological process. In this review, the pathophysiological concepts, relevance, diagnosis and management of patients with 'pseudoprogression' and 'pseudoresponse' are discussed. Guidelines are given with respect to radiological imaging modality, mode and frequency. Further biological and clinical insights into these phenomena require carefully designed prospective studies.

Irinotecan+5-fluorouracil with concomitant pre-operative radiotherapy in locally advanced non-resectable rectal cancer: a phase I/II study.

In the UK, 10% of patients diagnosed with rectal cancer have inoperable disease at presentation. This study ascertained whether the resectability rate of inoperable locally advanced rectal cancer was improved by administration of intravenous irinotecan, 5-fluorouracil (5-FU) and pelvic radiotherapy. During phase I of the trial (n=12), the dose of irinotecan was escalated in three-patient cohorts from 50 mg m(-2) to 60 mg m(-2) to 70 mg m(-2) to identify the maximum tolerated dose (60 mg m(-2)). In phase II, 31 patients with non-resectable disease received 45 Gy radiotherapy and 5-FU infusions (200 mg m(-2) per day) for 5 weeks. Irinotecan (60 mg m(-2)) was given on days 1, 8, 15 and 22. After treatment, patients were operated on if possible. Thirty patients completed the protocol, 28 underwent surgery. Before surgery, MRI restaging of 24 patients showed that 19 (79%) had a reduction in tumour stage after treatment (seven complete clinical response and 12 partial). Of 27 patients followed up after surgery, 22 (81%) had clear circumferential resection margins. Disease-free and overall survival estimates at 3 years were 65 and 90%, respectively. The regimen was well tolerated. Irinotecan, 5-FU and radiotherapy results in tumour downgrading, allowing resection of previously inoperable tumour with acceptable toxicity.

Expression of survivin, platelet-derived growth factor A (PDGF-A) and PDGF receptor alpha in primary central nervous system lymphoma.

PURPOSE: Primary central nervous system lymphomas (PCNSL) are rare tumours occurring in the brain. Their biology and the factors predicting survival are not well known. This study investigated expression of the antiapoptotic protein survivin and platelet-derived growth factor A (PDGF-A) and receptor (PDGFRalpha) in PCNSL. EXPERIMENTAL DESIGN: A total of 44 patients with histologically confirmed PCNSL treated between 1992 and 2004 were included in this study, and tumour specimens were investigated immunohistochemically for expression of survivin, PDGF-A and PDGFRalpha. Protein expression and clinical variables were analyzed statistically. RESULTS: Of the 44 tumours 43(98%) were diffuse large B-cell non-Hodgkin's lymphomas (NHL) and one was a T-cell NHL. Around 37 (84%) of the examined PCNSL specimens showed expression of survivin, 16 (36%) of PDGF-A and 34 (77%) of PDGFRalpha. Tumours expressing surviving co-expressed PDGFRalpha frequently and PDGF-A occasionally. Expression of the above proteins was not predictive for survival in this patient group. Except for age and therapy, no other clinical variables correlated significantly with overall survival. CONCLUSIONS: PCNSL express survivin and PDGFRalpha in the majority of investigated cases. PDGF-A is expressed less frequently. Immunohistochemical detection of these proteins does not correlate with overall survival and cannot be used as a prognostic factor.

Clinical use of genotype to predict chemosensitivity in oligodendroglial tumors.

BACKGROUND: The -1p/-19q genotype has been associated with prolonged survival and chemosensitivity in oligodendroglial neoplasms, but the predictive and prognostic significance of genotype in the routine clinic is not established. METHODS: The authors investigated allelic imbalance in 1p36, 19q13, 17p13, 10p12-15, and 10q22-26 and p53 mutation in a cohort representative of clinical practice at their center (50 primary, 26 recurrent cases) given PCV chemotherapy between 2000 and 2003 and compared with response and outcome following PCV. RESULTS: 1p/19q loss was found in 12/19 OII, 10/23 OAII, 11/13 OIII, and 6/21 OAIII. Response, seen in 92% with 1p/19q loss, was associated with the -1p/-19q genotype (Fisher exact: p < 0.001) regardless of WHO grade or whether primary or recurrent. 1p/19q loss was an independent prognostic factor associated with longer progression-free (PFS) and overall survival (OS) (Cox regression: PFS and OS p < 0.001), with greater impact on PFS than OS in primary tumors, and OS at recurrence. 17p13 loss and p53 mutation were associated with poor prognosis in recurrent tumors and chromosome 10 loss was associated with short PFS and OS in primary tumors. Histologic subtype did not influence outcome in tumors of equivalent genotype. Genotype had greater association with response and outcome than conventional clinical factors. A total of 29% with intact 1p/19q and a variety of genetic or clinicopathologic characteristics responded in association with increased PFS and OS. CONCLUSIONS: The -1p/-19q genotype predicted response and favorable outcome following PCV chemotherapy corroborating genetic analysis to guide routine clinical management. However, some cases with intact 1p/19q also had clinical benefit.

Genetic and metabolic predictors of chemosensitivity in oligodendroglial neoplasms.

The -1p/-19q genotype predicts chemosensitivity in oligodendroglial neoplasms, but some with intact 1p/19q also respond and not all with 1p/19q loss derive durable benefit from chemotherapy. We have evaluated the predictive and prognostic significance of pretherapy (201)Tl and (18)F-FDG SPECT and genotype in 38 primary and 10 recurrent oligodendroglial neoplasms following PCV chemotherapy. 1p/19q loss was seen in 8/15 OII, 6/15 OAII, 7/7 OIII, 3/11 OAIII and was associated with response (Fisher-Exact: P=0.000) and prolonged progression-free (log-rank: P=0.002) and overall survival (OS) (log-rank: P=0.0048). Response was unrelated to metabolism, with tumours with high or low metabolism showing response. Increased (18)F-FDG or (201)Tl uptake predicted shorter progression-free survival (PFS) in the series (log-rank: (201)Tl P=0.0097, (18)F-FDG P=0.0170) and in cases with or without the -1p/-19q genotype. Elevated metabolism was associated with shorter OS in cases with intact 1p/19q (log-rank: (18)F-FDG P=0.0077; (201)Tl P=0.0004) and shorter PFS in responders (log-rank: (18)F-FDG P=0.005; (201)Tl P=0.0132). (201)Tl uptake and 1p/19q loss were independent predictors of survival in multivariate analysis. In this initial study, (201)Tl and (18)F-FDG uptake did not predict response to PCV, but may be associated with poor survival following therapy irrespective of genotype. This may be clinically useful warranting further study.