L. Moonen

Squamous Cell Carcinoma of the Penis. III. Treatment of Regional Lymph Nodes

We analyzed the management of regional lymph nodes in 110 patients with squamous cell carcinoma of the penis treated at the Netherlands Cancer Institute between 1956 and 1989 with curative intent. Of 66 patients who presented with unsuspected nodes 57 were placed on a surveillance program, while lymph node dissection was performed in 5 (with adjuvant external radiation therapy in 1) and 4 were treated with external radiation therapy only. The management of 40 patients with clinically suspected nodes included surveillance in 5, lymph node dissection in 27 (with adjuvant radiotherapy in 11), biopsy in 4 and external radiation therapy in 4. Postoperative radiotherapy had been given if more than 2 nodes were involved or when extracapsular growth was observed. Overall, 25 patients had a regional recurrence, 5 of whom could be cured subsequently. All regional recurrences developed within 2 years after primary treatment. Analysis showed 100% survival in histologically proved node negative patients (stage pN0). The success of lymph node dissection was related to the extent of the metastatic spread and to the number of involved nodes. Patients with 1 positive node and unilateral inguinal involvement showed a statistically significant survival advantage compared to patients with more extensive spread. Considering the indications for node dissection we found a clear relationship among T category, grade and the probability of lymph node invasion. Patients with stage T1 tumors and stage T2, grades 1 and 2 tumors presented significantly less often with lymphatic invasion than those with other categories of disease and were less likely to have a regional recurrence after treatment of the primary tumor only. In these categories we recommend surveillance of the regional lymph nodes in patients who present with unsuspected nodes. However, patients with stage T2 grade 3, stage T3 and operable stage T4 tumors should undergo an immediate inguinal node dissection because of the high probability of clinically occult lymph node invasion (in our material more than 50%). With respect to the extent of the node dissection, we found that the likelihood of spread to the contralateral and/or pelvic regions was related to the number of invaded nodes in the inguinal region. We recommend contralateral node dissection and unilateral pelvic node dissection when 2 or more positive nodes are found in the dissected groin specimen. Primary pelvic node dissection should be performed in patients who present initially with cytologically or biopsy proved positive inguinal nodes.(ABSTRACT TRUNCATED AT 400 WORDS)

Squamous Cell Carcinoma of the Penis: Accuracy of Tumor, Nodes and Metastasis Classification System, and Role of Lymphangiography, Computerized Tomography Scan and Fine Needle Aspiration Cytology

Among 118 patients with squamous cell carcinoma of the penis treated at our cancer institute between 1956 and 1989, we analyzed the accuracy of classification, using the tumor, nodes and metastasis system. We analyzed the role of lymphography, computerized tomography and fine needle aspiration cytology as additional staging procedures. The primary tumor (T category) was classified incorrectly in 26% of the cases. Overstaging was noted in 10% of the cases because of unsuspected infiltration and overstaging was noted in 16%. Overstaging occurred because of edema and infection masking the actual size and giving a misconception of infiltration, and also because of primary presentation as large exophytic tumors with no or minimal histopathological infiltration. When the regional lymph nodes were categorized simply as positive or negative 80% of the tumors were classified correctly and 20% incorrectly (13% were false positive and 7% were false negative). Regional lymph node invasion that escaped clinical examination was not detected by any imaging examination or fine needle aspiration cytology study. Positive findings were found only in patients with clinically suspected nodes. The classification of regional nodes by clinical examination only is hardly improved by additional imaging studies. Clinical decisions with respect to the management of regional lymph nodes should not be based on negative findings of lymphangiography, computerized tomography or fine needle aspiration cytology. In patients with proved metastasis additional imaging may be of some help in the detection of pelvic node invasion and the determination of the extent of involvement. We recommend lymphangiography as the examination of choice.

Squamous cell carcinoma of the penis. II: Treatment of the primary tumor

The treatment of the primary tumor in 110 patients with squamous cell carcinoma of the penis seen between 1956 and 1989 was reviewed. Small tumors had generally been treated by penis conserving methods, such as circumcision, local excision and external radiotherapy alone or after circumcision or local excision. Since 1982 we have used the neodymium:YAG laser as a penis conserving method. In 51 patients (46%) penis conserving treatment had been performed and 59 (54%) had undergone some form of amputation. Overall, 16 of 110 patients (15%) had local recurrence. The risk of local recurrence after penis conserving therapy was significantly related to T category, with 10% local recurrences in stage T1 tumors in contrast to 32% and 100% in stages T2 and T3 tumors, respectively. All of the recurrences in patients with stage T1 tumors were strictly local and all were salvaged. In our view penis conserving therapy is a safe procedure in patients with stage T1 tumors and should always be attempted first. Amputation is considered to be overtreatment in these cases. Of 6 recurrences in the conservatively treated stage T2 disease group 4 were strictly local. These were all well or moderately differentiated tumors, not exceeding 3.5 cm. in diameter. We suggest penile conservation for this subgroup of T2 tumors. However, partial amputation is recommended for poorly differentiated stage T2 tumors. Local failure was observed in all stage T3 tumors treated with external radiation. In general, penis conservation in stage T3 tumors should not be attempted with the treatment modalities available to date. Comparing the different methods of penis conservation, used in 49 stages T1 and T2 tumors, no difference in local recurrence rate (18%) was observed among surgery, laser and external beam radiation. In view of the low morbidity, cutting and coagulation properties and minimal tissue changes, use of the neodymium:YAG laser would be our first choice of treatment modality. Penile conservation should be attempted only when frequent and long lasting followup is guaranteed, since local recurrences can appear as late as 8 years after primary treatment.

The use of a transverse CT image for the estimation of the dose given to the rectum in intracavitary brachytherapy for carcinoma of the cervix

BACKGROUND AND PURPOSE The three-dimensional (3D) dose distribution in combination with 3D anatomy of 13 patients treated for cervical carcinoma with intracavitary brachytherapy was analyzed. The aim of this study was to determine the correlation between a dose value obtained from the integral dose volume histogram (DVH) of the rectum and (a) the Nederlands Kanker Instituut (NKI) point of reference for the rectum dose (R) and (b) the highest dose to the frontal rectum wall in the transverse CT slice near the top of the vagina through point R. RESULTS The correlation between the DVH rectum dose value for 2 cm3 in the highest dose region and the rectum dose at point R was poor (regression coefficient 0.50). On the contrary, however, the correlation between the DVH rectum dose value for 2 cm3 in the highest dose region and the maximum rectum dose value in a transverse CT slice through point R was good (regression coefficient 0.90). CONCLUSIONS The maximal rectum dose value obtained from a transverse CT slice near the top of the vagina through point R was found to be a more representative point for the rectal dose burden and might therefore show a good correlation with complications. The point of reference for the rectal dose (R) was found not to be a reliable estimation of the maximal dose in the rectum.

Human tumour cell kinetics using a monoclonal antibody against iododeoxyuridine: Intratumour sampling variations

Cell kinetic parameters in human tumours were determined by in vivo labelling with iododeoxyuridine (IUdR) followed by flow cytometric analysis of tumour biopsies after staining with a monoclonal antibody against IUdR-DNA. The purpose of this study was to determine the variation in these kinetic parameters from area to area within the same tumour. Each patient received a single i.v. injection of IUdR and the biopsy or operation specimen was taken several hours later. Multiple biopsies were taken or the operation specimen was cut into several pieces. Tumour material was stored in ethanol. Each piece was subsequently processed and stained for analysis separately. The duration of DNA synthesis (Ts), the labelling index (L.I., percent IUdR-labelled cells) and the potential doubling time (Tpot) were determined for each sample. The mean and standard deviation (variation between pieces) for each parameter was calculated for each tumour. The coefficient of variation (C.V.) provided the measure of intratumoural variation. Thirteen tumours were investigated, 6 of which were transitional cell carcinomas of the bladder and 7 of which were squamous cell carcinomas, mostly of the head and neck. Ts values ranged from 4.1 to 17.2 h (mean 9.5 h), L.I. values from 1.6 to 18.6% (mean 9.7%) and Tpot values from 2.3 to 15.1 days (mean 7.2 days). Mean C.V.s for Ts, L.I. and Tpot were 10, 24 and 27%, respectively. Most of the variation in Tpot (calculated from the other two parameters), came from the L.I., with Ts showing much less intratumoural variations. It is concluded that this kinetic method using low IUdR doses can be successfully applied in human tumours and has sufficient accuracy for predictive assay applications in which tumours need to be classified according to their proliferation rates. Further developments are required to distinguish normal and malignant cells flow cytometrically, particularly for diploid tumours.

Cognitive complaints and cognitive impairment following BEP chemotherapy in patients with testicular cancer

Introduction. There is growing concern that some cytotoxic regimens for cancer affect cognitive functioning. This study examined the prevalence of cognitive complaints and deficits in testicular cancer (TC) patients treated with the worldwide standard BEP (bleomycin, etoposide and cisplatin) chemotherapy. Materials and methods. Seventy TC patients treated with BEP chemotherapy after surgery (S+CT) were examined with interviews and neuropsychological tests. These patients were compared with 57 TC patients treated with radiotherapy after surgery (S+RT) and with 55 TC patients that received surgery only (S). Patients were examined a median of 3 years after completion of treatment. Results. Thirty two percent of the S+CT patients reported cognitive complaints compared with 32% of the S+RT patients and 27% of the S patients (p=0.85). No differences in mean cognitive test performance were observed between the groups. On individual impairment scores, more S+CT patients showed cognitive dysfunction compared with S patients, but not compared with S+RT patients (S+CT versus S [p=0.038, OR=4.6, CI=1.1–19.7], S+CT versus S+RT [p=0.70, OR=0.8, CI=0.3–2.4] and S+RT versus S [p=0.070, OR=3.7, CI=0.8–15.7). Cognitive complaints were not related to cognitive test performance, but to emotional distress and fatigue. Discussion. Cognitive complaints are common among TC patients, independent of treatment modality. These complaints are related to emotional distress and fatigue and not to formal cognitive deficits. The finding of a small group of TC patients treated with chemotherapy exhibiting cognitive deficits should be confirmed in a prospective study before we can decide on its cause and relevance.

Prognostic factors in transitional cell cancer of the bladder: an emerging role for Bcl-2 and p53

BACKGROUND AND PURPOSE In a recent study on patients with transitional cell cancer of the bladder treated with curative radiotherapy following TUR-T, we demonstrated that a low apoptotic index and p53 positivity were associated with poor local control. The purpose of this study was to assess the prognostic significance of additional markers implicated in regulation of cell cycle and apoptosis. PATIENTS AND METHODS Bcl-2, Bax and p21 positivity were detected immunohistochemically on paraffin-embedded pre-treatment biopsies from 83 patients with invasive transitional cell cancer (TCC) of the bladder, treated with radiotherapy. In addition, markers determined in an earlier analysis, i.e.: p53, apoptotic index, cyclin D1, retinoblastoma protein and Ki-67 were included in the multivariate analysis. A stepwise proportional hazard analysis was performed, adjusting for classic prognostic factors (T-stage, grade, multifocality and macroscopic completeness of the TUR). Positivity was defined as >10% of tumor cells staining positive for Bcl-2, Bax and p21, and >20% for p53. RESULTS Bcl-2 positivity was found in 63%, Bax was positive in 52% and p21 in 55% of cases. In the PH analysis Bcl-2 positivity was found to be related to poor local control (36 vs. 72% at 3 years; P=0.003), as well as to shorter disease-specific survival (74 vs. 94% at 3 years; P=0.017). Evidence for an adverse effect of p53 positivity was also found (local control: 32 vs. 69% at 3 years;P=0.037, disease-specific survival: 76 vs. 92% at 3 years; P=0.043). In an additional PH analysis, we found poor local control rates for bladder cancers with combined Bcl-2 and p53 positivity (17 vs. 65% at 3 years; P=0.0017), and lower disease specific survival (60 vs. 92%; P=0.0024), disease-free survival (7 vs.35%, P=0.0023) and overall survival (39 vs. 80%; P=0.0018). CONCLUSION This study provides evidence for a poor outcome in patients treated with radiotherapy for TCC of the bladder expressing both Bcl-2 and p53. This relationship was found for local control and disease-free, disease-specific and overall survival.

Prognostic Significance of Extranodal Extension in Patients With Pathological Node Positive Penile Carcinoma

PURPOSE We assessed the prognostic significance of extranodal extension, defined as tumor extension through the lymph node capsule into the perinodal fibrous-adipose tissue, as well as several other risk factors in node positive penile cancer cases. MATERIALS AND METHODS We analyzed prospectively collected data on a consecutive series of 156 chemotherapy naïve patients with proven lymph node involvement who underwent therapeutic regional lymphadenectomy. Postoperative external radiotherapy was indicated when histopathological analysis revealed more tumor than 1 intranodal metastasis. We estimated cancer specific survival using the Kaplan-Meier method. Multivariate analysis was done according to the Cox proportional hazards model of factors statistically significant on univariate analysis. RESULTS Adjuvant radiotherapy was done in 70 patients (45%). Median followup was 57.8 months. Overall 5-year cancer specific survival was 61%. Men with extranodal extension had significantly decreased 5-year cancer specific survival compared with men without it (42% vs 80%). Other prognostic variables on univariate analysis were bilateral metastatic involvement vs unilateral, 3 or greater unilateral metastatic inguinal nodes vs 2 or fewer, inguinal lymphadenectomy positive margin status vs negative status and pelvic lymph node involvement. Pathological T stage or differentiation grade were not significant predictors of outcome. On multivariate analysis extranodal extension and pelvic lymph node involvement remained associated with decreased cancer specific survival (HR 2.37 and 2.20, respectively). CONCLUSIONS Metastatic inguinal lymph node extranodal extension and pelvic lymph node involvement are independent predictive parameters of cancer specific survival in patients with pathologically node positive penile carcinoma despite surgery with postoperative radiotherapy.

Apoptosis, proliferation and p53, cyclin D1, and retinoblastoma gene expression in relation to radiation response in transitional cell carcinoma of the bladder

PURPOSE To determine whether the apoptotic index, the Ki67 index, and the expression of the p53, cyclin D1, and retinoblastoma genes correlate with local control, overall survival, and time to distant metastases in invasive bladder cancer treated with external beam radiation. METHODS AND MATERIALS Paraffin-embedded pretreatment biopsies from 83 patients with invasive transitional cell carcinoma of the bladder were scored morphologically for apoptosis and immunohistochemically for Ki67, p53, cyclin D1, and retinoblastoma gene expression. Survival analysis methods were used to assess overall survival, local control, and freedom from distant metastases. A multiple proportional hazard (PH) regression analysis was performed to study the prognostic value of the abovementioned biologic parameters (all divided into two categories, except Ki67) in addition to classical prognostic factors such as T stage, histologic grade, multifocality of the tumor, and completeness of transurethral resection. All patients were treated with external beam radiation as sole treatment. Median follow-up for the 19 patients still living was 7.5 years. RESULTS Apoptotic index varied from 0% to 3.4% with a mean of 0.8% and a median of 0.6%. Ki67 index varied from 0% to 60% with a mean of 14% and a median of 12%. P53 protein was detectable in 61% of the tumors. Overexpression of cyclin D1 was observed in 39% of the tumors and loss of retinoblastoma protein in 23% of the tumors. High Ki67 index was found to be significantly associated with p53 expression (p = 0.04) and cyclin D1 overexpression (p = 0.023). Cyclin D1 overexpression was found more often in Rb-positive tumors than in Rb-negative tumors (p = 0.006). Other associations between the markers are less clear. Biologic markers were not correlated with T stage or grade. In the PH analysis local control was found to be significantly better for tumors with wild-type p53 (p = 0.028). Also, tumors with an apoptotic index above the median value (0.6%) had a significantly better local control rate (p = 0.035). Ki67 index (p = 0.35), retinoblastoma gene expression (p = 0.30) and cyclin D1 overexpression (p = 0.61) were not found to have an additional predictive value regarding local tumor control. None of the tested biologic parameters were found to be associated with overall survival. Time to distant metastases was significantly shorter for tumors with high Ki67 index (p = 0.01) and tumors with an apoptotic index less than median (p = 0.009). CONCLUSIONS The results of our study provide evidence for a prognostic value of p53 expression and apoptotic index with respect to the radiation response in bladder cancer in addition to more conventional prognosticators. The value of these parameters as a predictive assay for radiation response warrants confirmation in larger and prospective studies.

Muscle-invasive bladder cancer treated with external beam radiation: influence of total dose, overall treatment time, and treatment interruption on local control

PURPOSE To evaluate and eventually quantify a possible influence of tumor proliferation during the external radiation course on local control in muscle invasive bladder cancer. METHODS AND MATERIALS The influence of total dose, overall treatment time, and treatment interruption has retrospectively been analyzed in a series of 379 patients with nonmetastasized, muscle-invasive transitional cell carcinoma of the urinary bladder. All patients received external beam radiotherapy at the Netherlands Cancer Institute between 1977 and 1990. Total dose varied between 50 and 75 Gy with a mean of 60.5 Gy and a median of 60.4 Gy. Overall treatment time varied between 20 and 270 days with a mean of 49 days and a median of 41 days. Number of fractions varied between 17 and 36 with a mean of 27 and a median of 26. Two hundred and fourty-four patients had a continuous radiation course, whereas 135 had an intended split course or an unintended treatment interruption. Median follow-up was 22 months for all patients and 82 months for the 30 patients still alive at last follow-up. A stepwise procedure using proportional hazard regression has been used to identify prognostic treatment factors with respect to local recurrence as sole first recurrence. RESULTS One hundred and thirty-six patients experienced a local recurrence and 120 of these occurred before regional or distant metastases. The actuarial local control rate was 40.3% at 5 years and 32.3% at 10 years. In a multivariate analysis total dose showed a significant association with local control (p = 0.0039), however in a markedly nonlinear way. In fact only those patients treated with a dose below 57.5 Gy had a significant higher bladder relapse rate, whereas no difference in relapse rate was found among patients treated with doses above 57.5 Gy. This remained the case even after adjustment for overall treatment time and all significant tumor and patient characteristics. The Normalized Tumor Dose (NTD) (alpha/beta = 10) and NTD (alpha/beta = 15) were not significantly related to local control (p = 0.96 and p = 0.053, respectively). Only weak evidence was found for an association between local control and overall treatment time (p = 0.067). No difference in bladder relapse rate was found among patients treated with a continuous course and patients who had treatment interruptions (p = 0.099). Neither the length of the interruption, nor the actual number of treatment days has a significant influence on local control (p = 0.04 and p = 0.09, respectively). CONCLUSION In contrast to two earlier, but smaller reports, in this study no significant effect of treatment prolongation on outcome after radiotherapy could be demonstrated and thus no support was found for an important role for tumor proliferation as the cause of treatment failure in muscle-invasive bladder cancer. Results of large-sized phase III trials will have to be awaited to show any benefit from reduction of the overall treatment time and to quantify the potential effect of tumor proliferation.