Abderrahim Zouhair

CD4 and CD8 T-lymphocyte apoptosis can predict radiation-induced late toxicity: a prospective study in 399 patients.

Purpose: Predicting late effects in patients treated with radiation therapy by assessing in vitro radiation-induced CD4 and CD8 T-lymphocyte apoptosis can be useful in individualizing treatment. Experimental Design: In a prospective study, 399 curatively irradiated patients were tested using a rapid assay where fresh blood samples were in vitro irradiated with 8 Gy X-rays. Lymphocytes were collected and prepared for flow cytometric analysis. Apoptosis was assessed by associated condensation of DNA. The incidences of late toxicities were compared for CD4 and CD8 T-lymphocyte apoptoses using receiver-operating characteristic curves and cumulative incidence. Results: No association was found between early toxicity and T-lymphocyte apoptosis. Grade 2 and 3 late toxicities were observed in 31% and 7% of patients, respectively. More radiation-induced T-lymphocyte apoptosis was significantly associated with less grade 2 and 3 late toxicity (Grays test, P < 0.0001). CD8 (area under the curve = 0.83) was more sensitive and specific than CD4. No grade 3 late toxicity was observed for patients with CD4 and CD8 values greater than 15% and 24%, respectively. The 2-year cumulative incidence for grade 2 or 3 late toxicity was 70%, 32%, and 12% for patients with absolute change in CD8 T-lymphocyte apoptosis of ≤16, 16 to 24, and >24, respectively. Conclusions: Radiation-induced T-lymphocyte apoptosis can significantly predict differences in late toxicity between individuals. It could be used as a rapid screen for hypersensitive patients to radiotherapy. In future dose escalation studies, patients could be selected using the apoptosis assay.

Prognostic factors in urothelial renal pelvis and ureter tumours: A multicentre rare cancer network study

To assess the prognostic factors in patients with transitional-cell carcinoma of the renal pelvis and/or ureter, a series of 138 patients with transitional-cell carcinoma of the renal pelvis and/or ureter was collected in a retrospective multicentre study. 12 patients with distant metastases were excluded from the statistical evaluation. All but 3 patients underwent radical surgery: nephroureterectomy (n = 71), nephroureterectomy and lymphadenectomy (n = 20), nephroureterectomy and partial bladder resection or transurethral resection (n = 20), nephrectomy (n = 10), and ureterectomy (n = 5). Sixty-one per cent (n = 77) of the tumours were located in the renal pelvis, and 21% (n = 27) in the ureter (both in 22 [17%]). Following surgery, residual tumour was still present in 33 patients (16 microscopic and 17 macroscopic). Postoperative radiotherapy was given to 45 (36%) patients. The median follow-up period was 39 months. In a median period of 9 months, 66% of the patients relapsed (34 local, 7 locoregional, 16 regional, and 24 distant). The 5- and 10-year survival were 29% and 19%, respectively, in all patients. In univariate analyses, statistically significant factors influencing the outcome were Karnofsky index, pT-classification, pN-classification, tumour localisation, grade, and residual tumour after surgery. Multivariate analysis revealed that independent prognostic factors influencing outcome were pT-classification, the existence of residual tumour, and tumour localisation. In patients with urothelial renal pelvis and/or ureter tumours, a radical surgical attitude is mandatory; and the presence of tumour in the ureter is associated with a poorer prognosis.

Outcome and prognostic factors in orbital lymphoma: a Rare Cancer Network study on 90 consecutive patients treated with radiotherapy.

PURPOSE To assess the outcome and prognostic factors in patients with orbital lymphoma treated by radiotherapy (RT). METHODS AND MATERIALS Between 1980 and 1999, 90 consecutive patients with primary orbital lymphoma were treated in 13 member institutions of the Rare Cancer Network. A full staging workup was completed in 56 patients. Seventy-eight patients had low-, 6 intermediate-, and 6 high-grade lymphoma, and 75 had a single orbital localization. All patients underwent RT with a median dose of 34.2 Gy (range 4.0-50.4). Eleven patients received chemotherapy in addition to RT. RESULTS After RT, local control was achieved in 97% of the patients. Local progression occurred in 2% and local relapse 1%. The rate of systemic relapse was 20%, and 9% of the patients developed metachronous contralateral eye involvement. The 5-year disease-free survival, overall survival, and cause-specific survival rate was 65%, 78%, and 87%, respectively. In univariate analyses, the statistically significant favorable prognostic factors were younger age, low grade, normal erythrocyte sedimentation rate, absence of muscular infiltration, complete response to treatment, conjunctival localization, and normal lactate dehydrogenase value for overall survival, disease-free survival, and freedom from treatment failure. In multivariate analysis, the favorable factors were younger age and low grade for overall and disease-free survival; a favorable response, conjunctival localization, and complete staging were highly significant for disease-free survival and freedom from treatment failure. Neither the RT technique nor the total dose influenced the outcome. Cataract and xerophthalmia were the most prominent late toxicities. CONCLUSION Moderate- to low-dose RT alone is able to control primary orbital lymphoma with low morbidity. A full staging workup is warranted in these patients. Prognostic factors were identified that could be useful in the overall management of this uncommon site of primary lymphoma.

The epidermal growth factor receptor (EGFR) in head and neck cancer: its role and treatment implications

Epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptors. Its stimulation by endogenous ligands, EGF or transforming growth factor-alpha (TGF-α) results in activation of intracellular tyrosine kinase, therefore, cell cycle progression. High levels of EGFR expression are correlated with poor prognosis and resistance to radiation therapy in a variety of cancers, mostly in squamous-cell carcinoma of the head and neck (SCCHN). Blocking the EGFR by a monoclonal antibody results in inhibition of the stimulation of the receptor, therefore, in inhibition of cell proliferation, enhanced apoptosis, and reduced angiogenesis, invasiveness and metastases. The EGFR is a prime target for new anticancer therapy in SCCHN, and other agents in development include small molecular tyrosine kinase inhibitors and antisense therapies.

Concomitant Use of Tamoxifen with Radiotherapy Enhances Subcutaneous Breast Fibrosis in Hypersensitive Patients

Concomitant use of adjuvant tamoxifen (TAM) and radiation therapy (RT) is not widely accepted. We aim to assess whether this treatment is associated with an increased risk of developing subcutaneous fibrosis after conservative or radical surgery in breast cancer patients. We analysed 147 women with breast cancer treated with adjuvant RT, and who were included in the KFS 00539-9-1997/SKL 00778-2-1999 prospective study aimed at evaluating the predictive value of CD4 and CD8 T-lymphocyte apoptosis for the development of radiation-induced late effects. TAM (20 mg day−1) with concomitant RT was prescribed in 90 hormone receptor-positive patients. There was a statistically significant difference in terms of complication-relapse-free survival (CRFS) rates at 3 years, 48% (95% CI 37.2–57.6%) vs 66% (95% CI 49.9–78.6%) and complication-free survival (CFS) rates at 2 years, 51% (95% CI 40–61%) vs 80% (95% CI 67–89%) in the TAM and no-TAM groups, respectively. In each of these groups, the CRFS rates were significantly lower for patients with low levels of CD8 radiation-induced apoptosis, 20% (95% CI 10–31.9%), 66% (95% CI 51.1–77.6%), and 79% (95% CI 55–90.9%) for CD8 ⩽16, 16–24, and >24%, respectively. Similar results were observed for the CFS rates. The concomitant use of TAM with RT is significantly associated with an increased incidence of grade 2 or greater subcutaneous fibrosis; therefore, caution is needed for radiosensitive patients.

Prognostic factors in solitary plasmacytoma of the bone: a multicenter Rare Cancer Network study

BackgroundSolitary plasmacytoma (SP) of the bone is a rare plasma-cell neoplasm. There are no conclusive data in the literature on the optimal radiation therapy (RT) dose in SP. Therefore, in this large retrospective study, we wanted to assess the outcome, prognostic factors, and the optimal RT dose in patients with SP.MethodsData from 206 patients with bone SP without evidence of multiple myeloma (MM) were collected. Histopathological diagnosis was obtained for all patients. The majority (n = 169) of the patients received RT alone; 32 chemotherapy and RT, and 5 surgery. Median follow-up was 54 months (7–245).ResultsFive-year overall survival, disease-free survival (DFS), and local control was 70%, 46%, and 88%; respectively. Median time to MM development was 21 months (2–135) with a 5-year probability of 51%. In multivariate analyses, favorable factors were younger age and tumor size < 5 cm for survival; younger age for DFS; anatomic localization (vertebra vs. other) for local control. Older age was the only predictor for MM. There was no dose-response relationship for doses 30 Gy or higher, even for larger tumors.ConclusionYounger patients, especially those with vertebral localization have the best outcome when treated with moderate-dose RT. Progression to MM remains the main problem. Further investigation should focus on adjuvant chemotherapy and/or novel therapeutic agents.

Radiation therapy alone or combined surgery and radiation therapy in squamous-cell carcinoma of the penis?

To assess the prognostic factors and the outcome in patients with squamous-cell carcinoma of the penis, a retrospective review of 41 consecutive patients with non-metastatic invasive carcinoma of the penis, treated between 1962 and 1994, was performed. The median age was 59 years (range: 35-76 years). According to the International Union Against Cancer (UICC) 1997 classification, there were 12 (29%) T1, 24 (59%) T2, 4 (10%) T3 and 1 TX (2%) tumours. The N-classification was distributed as follows: 29 (71%) patients with N0, 8 (20%) with N1, 3 (7%) with N2 and 1 (2%) with N3. Forty-four per cent (n=18) of the patients underwent surgery: partial penectomy with (n=4) or without (n=12) lymph node dissection, or total penectomy with (n=1) or without (n=1) lymph node dissection. 23 patients were treated with radiation therapy alone, and all but 4 of the patients who were operated upon received postoperative radiation therapy (n=14). The median follow-up period was 70 months (range 20-331 months). In a median period of 12 months (range 5-139 months), 63% (n=26) of the patients relapsed (local in 18, locoregional in 2, regional in 3 and distant in 3). Local failure (stump in the operated patients, and the tumour bed in those treated with primary radiation therapy) was observed in 4 out of 16 (25%) patients treated with partial penectomy +/-postoperative radiotherapy versus 14 out of 23 (61%) treated with primary radiotherapy (P=0.06). 15 (83%) out of 18 local failures were successfully salvaged with surgery. In all patients, 5- and 10-year survival rates were 57% (95% confidence interval (CI), 41-73%) and 38% (95% CI, 21-55%), respectively. The 5-year local and locoregional rates were 57% (95% CI, 41-73%) and 48% (95% CI, 32-64%), respectively. In patients treated with primary radiotherapy, 5- and 10-year probabilities of surviving with penis preservation were 36% (95% CI, 22-50%) and 18% (95% CI, 2-34%), respectively. In multivariate analyses, survival was significantly influenced by the N-classification, and surgery was the only independent factor predicting the locoregional control. We conclude that, in patients with squamous-cell carcinoma of the penis, local control is better in patients treated with surgery. However, there seems to be no difference in terms of survival between patients treated by surgery and those treated by primary radiotherapy +/-salvage surgery, with 39% having organ preservation.

Management of primary anal canal adenocarcinoma: A large retrospective study from the Rare Cancer Network

PURPOSE Primary adenocarcinoma of the anus is a rare tumor. The current standard treatment consists of abdominoperineal resection (APR). The aim of this Rare Cancer Network study was to evaluate the prognostic factors and outcome after the three most commonly used treatment approaches. METHODS AND MATERIALS This multicenter study collected data from 82 patients: 15 with T1 (18%), 34 with T2 (42%), 22 with T3 (27%), and 11 with T4 (13%) tumors according to the TNM classification (International Union Against Cancer, 1997). Patients were separated into, and analyzed according to, three treatment categories: radiotherapy/surgery (RT/S group, n = 45), combined radiochemotherapy (RT/CHT group, n = 31), and APR alone (APR group, n = 6). The main patient characteristics were evenly distributed among the three groups. RESULTS The actuarial locoregional relapse rate at 5 years was 37%, 36%, and 20%, respectively, in the RT/S, RT/CHT, and APR groups (RT/S vs. RT/CHT, p = 0.93; RT/CH vs. APR, p = 0.78). The 3-, 5-, and 10-year overall survival rate was 47%, 29%, and 23% in the RT/S group, 75%, 58%, and 39% in the RT/CHT group, and 42%, 21%, and 21% in the APR group (RT/CHT vs. RT/S, p = 0.027), respectively. The 5- and 10-year disease-free survival rate was 25% and 18% in the RT/S group, 54% and 20% in the RT/CHT group, and 22% and 22% in the APR group (RT/CHT vs. RT/S, p = 0.038), respectively. Multivariate analysis revealed four independent prognostic factors for survival: T stage, N stage, histologic grade, and treatment modality. CONCLUSION Primary adenocarcinoma of the anal canal requires rigorous management. Multivariate analysis showed that T and N stage, histologic grade, and treatment modality are independent prognostic factors for survival. We observed better survival rates after combined RT/CHT. We also recommend using APR only for salvage treatment.

Prognostic impact of epidermal growth factor receptor (EGFR) expression on loco-regional recurrence after preoperative radiotherapy in rectal cancer.

BackgroundEpidermal growth factor receptor (EGFR) represents a major target for current radiosensitizing strategies. We wished to ascertain whether a correlation exists between the expression of EGFR and treatment outcome in a group of patients with rectal adenocarcinoma who had undergone preoperative radiotherapy (RT).MethodsWithin a six-year period, 138 patients underwent preoperative radiotherapy and curative surgery for rectal cancer (UICC stages II-III) at our institute. Among them, 77 pretherapeutic tumor biopsies were available for semi-quantitative immunohistochemical investigation evaluating the intensity and the number (extent) of tumor stained cells. Statistical analyses included Cox regression for calculating risk ratios of survival endpoints and logistic regression for determining odds ratios for the development of loco-regional recurrences.ResultsMedian age was 64 years (range: 30–88). Initial staging showed 75% and 25% stage II and III tumors, respectively. RT consisted of 44-Gy pelvic irradiation in 2-Gy fractions using 18-MV photons. In 25 very low-rectal-cancer patients the primary tumor received a boost dose of up to 16 Gy for a sphincter-preservation approach. Concomitant chemotherapy was used in 17% of the cases. All patients underwent complete total mesorectal resection. Positive staining (EGFR+) was observed in 43 patients (56%). Median follow-up was 36 months (range: 6–86). Locoregional recurrence rates were 7 and 20% for EGFR extent inferior and superior to 25%, respectively. The corresponding locoregional recurrence-free survival rate at two years was 94% (95% confidence interval, CI, 92–98%) and 84% (CI 95%, 58–95%), respectively (P = 0.06). Multivariate analyses showed a significant correlation between the rate of loco-regional recurrence and three parameters: EGFR extent superior to 25% (hazard ratio = 7.18, CI 95%, 1.17–46, P = 0.037), rectal resection with microscopic residue (hazard ratio = 6.92, CI 95%, 1.18–40.41, P = 0.032), and a total dose of 44 Gy (hazard ratio = 5.78, CI 95%, 1.04–32.05, P = 0.045).ConclusionEGFR expression impacts on loco-regional recurrence. Knowledge of expression of EGFR in rectal cancer could contribute to the identification of patients with an increased risk of recurrences, and to the prediction of prognosis.

Outcome and patterns of failure in testicular lymphoma: a multicenter rare cancer network study

PURPOSE To assess the outcome and patterns of failure in patients with testicular lymphoma treated by chemotherapy (CT) and/or radiation therapy (RT). METHODS AND MATERIALS Data from a series of 36 adult patients with Ann Arbor Stage I (n = 21), II (n = 9), III (n = 3), or IV (n = 3) primary testicular lymphoma, consecutively treated between 1980 and 1999, were collected in a retrospective multicenter study by the Rare Cancer Network. Median age was 64 years (range: 21-91 years). Full staging workup (chest X-ray, testicular ultrasound, abdominal ultrasound, and/or thoracoabdominal computer tomography, bone marrow assessment, full blood count, lactate dehydrogenase, and cerebrospinal fluid evaluation) was completed in 18 (50%) patients. All but one patient underwent orchidectomy, and spermatic cord infiltration was found in 9 patients. Most patients (n = 29) had CT, consisting in most cases of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) with (n = 17) or without intrathecal CT. External RT was delivered to scrotum alone (n = 12) or testicular, iliac, and para-aortic regions (n = 8). The median RT dose was 31 Gy (range: 20-44 Gy) in a median of 17 fractions (10-24), using a median of 1.8 Gy (range: 1.5-2.5 Gy) per fraction. The median follow-up period was 42 months (range: 6-138 months). RESULTS After a median period of 11 months (range: 1-76 months), 14 patients presented lymphoma progression, mostly in the central nervous system (CNS) (n = 8). Among the 17 patients who received intrathecal CT, 4 had a CNS relapse (p = NS). No testicular, iliac, or para-aortic relapse was observed in patients receiving RT to these regions. The 5-year overall, lymphoma-specific, and disease-free survival was 47%, 66%, and 43%, respectively. In univariate analyses, statistically significant factors favorably influencing the outcome were early-stage and combined modality treatment. Neither RT technique nor total dose influenced the outcome. Multivariate analysis revealed that the most favorable independent factors predicting the outcome were younger age, early-stage disease, and combined modality treatment. CONCLUSIONS In this multicenter retrospective study, CNS was found to be the principal site of relapse, and no extra-CNS lymphoma progression was observed in the irradiated volumes. More effective CNS prophylaxis, including combined modalities, should be prospectively explored in this uncommon site of extranodal lymphoma.