Predictive and prognostic markers in a series of patients with head and neck squamous cell invasive carcinoma treated with concurrent chemoradiation therapy.

It has been proposed that diverse anticancer drugs and radiation therapy may induce a mode of cell death with the characteristics of apoptosis. Since apoptosis is under the control of several oncogenes, we analyzed the expression of the protein encoded by the proto-oncogenes bcl-2 and p53. Furthermore, we studied cell proliferation [using PC-10 mAb to proliferating cell nuclear antigen (PCNA)] and vascularization [using the CD-31 mAb and by counting intratumoral microvessel density (IMD)] using immunocytochemistry. A series of 73 patients with clinical stage II-IV squamous cell invasive carcinoma of the head and neck (H&N) were treated with concurrent chemoradiation therapy (cisplatin, 80 mg/m2, versus carboplatin, 375 mg/m2, three times every 3 weeks and a total dose of radiation therapy of 64 Gy in 6-8 weeks). We correlated the expression of these markers, determined prior to treatment, with response to the therapy and prognosis. Bcl-2 protein was expressed in 37.4% of the carcinomas (25/67 evaluable), and it was not significantly associated with any other feature studied. Forty (56. 4%) of the 71 carcinomas evaluable for p53 were p53 positive; the median IMD was 38 microvessels/field at the hot spot (range, 18-80), and the median percentage of nuclei labeled by the PC-10 mAb was 50% (range, 0-95%). In the univariate analysis, regional lymph node negativity (P = 0.016), good performance status (PS) (PS >/= 90; P = 0.044), bcl-2 positivity (P = 0.070), and low vascularization (P = 0. 085) were significantly associated with a higher probability of complete remission. In the multivariate analysis (final model), only IMD (continuous variable; P = 0.045) and PS (P = 0.017) retained significance. As far as prognosis is concerned, in the univariate analysis, patients with tumors with low histological grading (grades 1-2; P = 0.006), p53 negative (P = 0.09), bcl-2 positive (P = 0.08), and high PCNA labeling (P = 0.06) had a significantly better disease-free survival. In the multivariate analysis, only grading (P = 0.003) and p53 (P = 0.04) retained significance for disease-free survival. For overall survival, in the univariate analysis, the following markers were significantly prognostic when only deaths due to progression are considered: response to therapy (P = 0.00001), PS (P = 0.04), nodal status (P = 0.028), PCNA (P = 0.04), p53 (P = 0. 08), and grading (P = 0.01). In the multivariate analysis, only patients who achieved complete response (P = 0.00002), high PCNA values (P = 0.002), and low histological grading (P = 0.01) retained a statistically significant probability of better overall survival. Our results suggest that in this series of H&N cancer patients the markers capable of predicting response to therapy are distinct from those associated with prognosis, once the remission has been achieved. This information is potentially useful to the clinician for developing a more rational therapeutic approach for H&N cancer patients eligible for concurrent chemoradiation therapy.

Evaluation of linear accelerator radiosurgical techniques using biophysical parameters (NTCP and TCP).

PURPOSE: Several irradiation techniques are compared with regard to normal tissue complication probability and tumor control probability. METHODS AND MATERIALS: Normal tissue complication probability is calculated using a model based on the "critical element architecture." The probability of controlling an inhomogeneously irradiated tumor is calculated using a model that takes into account the heterogeneity of tumors (different radiosensitivity of clonogens within the tumor and the varying number of clonogens among patients with the same kind of tumor). The ratio of tumor control probability to normal tissue complication probability (therapeutic gain factor) at different levels of dose has been used as a score for the analysis of various irradiation techniques. RESULTS: The best irradiation techniques depends on many factors: irradiation genometry, irradiation field size, choice of the reference isodose, and it is dictated by the pathology of the lesions (noninfiltrating radioresistant tumors, infiltrating radioresistant tumors, noninfiltrating radiosensitive tumors, infiltrating radiosensitive tumors, arterovenous malformations). For the irradiation of the artero-venous malformations it is proposed to insert on the supplemental collimator a flattening filter to reduce the probability of inducing a poorly syncronized obliterative effect. CONCLUSION: We propose that for each kind of pathology to be treated radiosurgically, a proper irradiation strategy should be used.

Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study.

PURPOSE: To evaluate the efficacy and toxicity of single-agent vinorelbine (VNB), a semisynthetic vinca alkaloid, in patients with breast cancer previously treated with other chemotherapeutic regimens for metastatic disease. PATIENTS AND METHODS: Sixty-seven of 70 patients with assessable disease entered onto the study were assessable. The main characteristics were as follows: median age, 60 years (range, 41 to 77); median performance status (PS; Karnofsky score), 90 (range, 60 to 100); and number of previous chemotherapeutic regimens given--one in 17, two in 27, three in eight, four in two, and five in one patient. The dominant sites of metastasis were viscera in 40, bone in 16, and soft tissues in 11 patients. VNB was administered beginning with the dose of 20 mg/m2 by 60-minute intravenous (iv) infusion weekly, with a dose escalation up to 25 mg/m2 if the first four courses were well tolerated. The treatment was continued until disease progression. RESULTS: Overall, 845 courses of VNB were given (median, 10; range, eight to 33). Objective responses were as follows: complete response (CR) in three (4.5%), partial response (PR) in 21 (31.2%), stable disease (SD) in 20 (30%), and progressive disease (PD) in 23 patients (34.3%). Twenty-four of 67 assessable patients obtained a major objective response (CR or PR, 36%; 95% confidence interval [Cl], 24% to 47%). Thirty-three percent of patients had a > or = 33% reduction of dose-intensity (DI). The median time to progression was 18 weeks. The drug was active in patients pretreated with either cyclophosphamide, methotrexate, and fluorouracil (CMF) or anthracyclines. The most relevant toxicity observed was myelosuppression: 17 (25%) and 19 patients (28%) had World Health Organization grade III, and six (9%) and six patients (9%) had grade IV leukopenia and granulocytopenia, respectively; two (3%) and two patients (3%) had grade III and IV anemia, respectively. Nonhematologic toxicities were phlebitis (grade II or III in 15 patients), alopecia (grade I or II in 16), nausea and vomiting (grade II or III in 15), diarrhea (grade II in two), constipation (grade II or III in 16), stomatitis (grade II or III in 13), peripheral neuropathy (grade II in seven), and asthenia (grade II in five). CONCLUSION: This study shows that VNB is an effective and well-tolerated agent in pretreated patients with advanced breast cancer. This drug does not seem to present cross-resistance with previous CMF or anthracycline regimens. Future clinical trials should be designed to prove whether the inclusion of VNB in combination chemotherapy regimens, or whether an enhancement of its dose-intensity using bone marrow growth factors, is able to improve further the efficacy of this drug in breast carcinoma.

Vinorelbine in pre-treated advanced head & neck squamous cell carcinoma. A phase II study.

BACKGROUND: There are few moderately active single-agents for the treatment of recurrent or metastatic head & neck cancer. Thus, the identification of novel active agents is warranted. We performed the present phase II trial to evaluate activity and toxicity of vinorelbine (VNB) in previously treated patients with advanced head & neck cancer. PATIENTS AND METHODS: 16 patients entered the study, 15 of whom were evaluable. The main characteristics were: M/F = 14/1; median age of 58 yrs (18-67); median PS (Karnofsky score) of 70 (60-100); primitive tumor sites were: oropharynx in 5; larynx in 4, hypopharynx in 3, rhynopharynx in 2, and oral cavity in 1 patient; initial clinical stage was IV in 9, III in 4 and II in 2 patients. Previous treatments were: cisplatinum with concurrent radiotherapy in 6 and cisplatinum + fluorouracil (for at least 2 cycles) in 9 patients. VNB was given at the dose of 20 mg/m2 i.v. infusion for 1 hr, weekly, for a minimum of 8 doses. Response and toxicity were evaluated after at least 8 doses of VNB. RESULTS: Overall, 139 courses of VNB were given (median 9, range 8-19). Objective responses were: partial response in 1 patient (6%); stable disease, lasting at least 2 months, in 4 patients (27%) and progression in the other 10 patients (67%). Three patients had a one week delay in subsequent courses due to severe hematological toxicity. Toxicities observed were: leucopenia of grade IV (W.H.O.) in 2 patients and of grade I-II in 12 patients; granulocytopenia of grade III in 1 patient and of grade IV in 2 patients; grade I-II anemia in 4 patients; grade II phlebitis in 3 patients; grade II constipation in 2 patients, grade I-II peripheral neuropathy in 3 patients, grade I-II nausea and vomiting in 4 patients, and grade II stomatitis in 2 patients. CONCLUSIONS: VNB, in this series of heavily pre-treated patients with head & neck cancer, did not reveal an antitumor activity of interest.

Intratumoral microvessel density and p53 protein: correlation with metastasis in head-and-neck squamous-cell carcinoma.

Squamous-cell carcinoma of the head and neck includes a heterogeneous group of tumours of the upper air and food passages for which prognosis is difficult to assess. In fact, patients in comparable stages may have diverse clinical courses and responses to similar treatments. In order to better define the prognosis of each patient there is therefore a need to identify novel biological markers which reflect more accurately growth rate, progression and metastatic potential of each tumour. We assessed whether metastases correlate with microvessel counts (i.e. intratumoral vascularity) using the CD-31 monoclonal antibody (MAb) and p53 mutant protein expression, determined in the primary by immunocytochemical methods in 70 patients with locally advanced head and neck cancer. Patients were treated with concurrent chemo-radiotherapy; 50 of these presented loco-regional node metastasis at diagnosis whereas 3 cases, initially node-negative, developed distant metastasis during the period of observation. No feature was predictive for objective response to treatment. The overall mean and median blood vessel density at "hot spots" was 37.42 and 36, respectively, and 57% of the tumours expressed p53 mutant proteins. These 2 biological markers were significantly associated. Patients with metastases (loco-regional and distant) had a significantly higher mean blood-vessel density than those without tumour spread. Also, patients with p53-positive (+/++) tumours had a significantly higher incidence of metastasis than those with negative ones. Multivariate analysis showed that both vascularity and stage, but not p53 expression, are significant and independent predictors of metastasis in this series.

Treatment of locally advanced squamous-cell carcinoma of the head and neck with concurrent radiochemotherapy - randomized comparison of Cisplatin versus Carboplatin.

Several phase II studies have shown that concurrent chemotherapy and radiotherapy (RT) improves the response rates and locoregional control in patients with advanced, unresectable squamous-cell carcinoma of the head and neck (H&N). However, it is still unclear which is the drug of choice to be given with RT. We therefore conducted a randomized comparison of cisplatin (CDDP)-RT versus carboplatin (CRP)-RT in such patients. The two platinum compounds were given at equitoxic doses. The primary objective of the study was to compare the side effects and the response rates of the two regimens. Radiotherapy was given at conventional dosages, 2 Gy for 5 days every week for a total dose of 64 Gy with CDDP 80 mg/m2 or CRP 375 mg/m2 for three cycles on days 1, 21 and 42. At present 53 patients are entered in the study: 27 in the CDDP arm and 26 in the CRP. The two arms were balanced for all the pre-treatment characteristics. Both the schedules were well tolerated. However, incidence of nausea and vomiting (p=0.0045); anemia (p=0.032) and peripheral neuropathy (p=0.032) was significantly greater with CDDP-RT as compared to CRP-RT. On the other hand, CRP-RT gives a significantly higher incidence of stomatitis (p=0.0067) and a marginally worse thrombocytopenia (p=0.09). The complete response (CR) rates were similar in the two arms (55.5% in the CDDP-RT versus 61.5% in that CRP-RT, respectively) as well as the overall response rates (92.5% versus 84.5%, respectively; p=0.36). The estimated 1 -and 2 year overall and disease-free survival rates were not significantly different in the two arms. In both the groups logistic-regression models showed that those patients with a CR (p=0.017); stage III (p=0.011); smaller primary (p=0.025) and limited node-involvement (p<0.001) had a significant better survival. We conclude that concurrent chemo-radiotherapy is an effective and safe treatment for patients with locally advanced H&N cancer. The combination CRP-RT possess a similar activity but a different, and perhaps a more favorable, spectrum of toxicity when compared to the CDDP-RT therapy. Survival results need to be assessed in a larger series and followed for a more prolonged time.

Surgical and adjuvant radiation therapy of resectable retroperitoneal soft tissue sarcomas in adults.

Primary soft tissue sarcoma of the retroperitoneum is a rare disease. A series of 11 evaluable adult patients with retroperitoneal soft tissue sarcomas is reported. These patients were treated with complete surgery and adjuvant radiation therapy (total dose from 50 to 64 Gy) using an 18 MeV linear accelerator. After a median follow-up of 48 months (range, 6-84), 4 patients had a local-regional recurrence, 3 had distant metastases, and 4 died of progressive disease. Four-year estimated disease-free survival was 54.5% and overall survival was 70%. Treatment was well tolerated by most patients: 7 patients experienced moderate gastrointestinal toxicity, mainly nausea and diarrhea, during radiotherapy; 2 cases had weight loss > 15% at the end of the therapy; and chronic ileitis was observed in 2 cases. We conclude that adjuvant radiotherapy seems to reduce the incidence of local-regional recurrences in these patients. No radiation-induced irreversible injury was observed, but one young woman had amenorrhea after radiotherapy. Controlled clinical trials are warranted to define the role and effectiveness of adjuvant radiotherapy and/or chemotherapy in retroperitoneal soft tissue sarcomas.

Synchronous radiotherapy and chemotherapy with cisplatin in the management of locally advanced or recurrent head and neck cancer.

A synergism between cisplatin and radiotherapy has been demonstrated in in vitro and in vivo studies. To improve the locoregional control of disease and the survival rate in patients affected by locally advanced or recurrent squamous cell carcinoma of the head and neck, we planned a Phase II study of concurrent radiotherapy, 2 Gy for 5 days every week for a total dose of 60-70 Gy with cisplatin 80 mg/m2 every 21 days for 2 or 3 doses (on days 1, 21, 42). Fifty-one patients were entered in the study; 48 were evaluable for response and toxicity; 18 (37.5%) had untreated Stage III disease; 25 (52%) had Stage IV disease; 5 (10.5%) had recurrent disease. The complete response rate in Stage III-IV patients was 63% (27 of 43) with 95% confidence limits from 48 to 77% (+/- 14.5%). In the group of five patients with recurrent disease, only one (20%) achieved a complete response. In patients with Stage III-IV disease, a significantly higher complete response rate was observed for those younger than 58.5 years (p = 0.05). The overall estimated 1- and 2-year survival was 59% and 37%, respectively, and a significantly better survival was observed in complete responders compared to partial responses or patients with stable disease (p = 0.037). Disease-free survival was 46% and 36% at 1 and 2 years, respectively. Distant failure occurred only in 12.5% of the patients. Overall, the treatment was well tolerated, and only three patients refused to complete the planned therapy. Gastrointestinal and hematological toxicity were the most common side effects. Data from present trial were compared with that of 50 patients with comparable characteristics treated with radiotherapy alone from 1985 to 1987 as a historical control. The complete response rate, the disease-free survival, and the overall survival appear to be better in the patients treated with chemoradiotherapy. It was concluded that the combination of chemoradiotherapy in patients with Stage III-IV head and neck squamous cell carcinoma is an effective and safe treatment with an apparent better locoregional control than radiotherapy alone. Survival results need to be evaluated in a Phase III randomized trial.

Human breast cancer: prognostic significance of the c-erbB-2 oncoprotein compared with epidermal growth factor receptor, DNA ploidy, and conventional pathologic features.

PURPOSE: A study was undertaken to define the prognostic value of the expression of the c-erbB-2 oncoprotein in a series of breast cancer patients when compared by multivariate analysis with expression of the epidermal growth factor receptor (EGFR), DNA ploidy, and conventional clinicopathologic features. PATIENTS AND METHODS: Prognostic indicators were analyzed in 165 primary breast cancers. The c-erbB-2 oncoprotein was recognized by the polyclonal antibody 21N using an immunocytochemical method. Expression of the EGFR was stated immunocytochemically using the monoclonal antibody EGFR1. DNA ploidy was assessed in paraffin-embedded sections using a standard flow-cytometric method. RESULTS: Overall, 27% of carcinomas had membrane 21N-staining and were classified as c-erbB-2-positive. Overexpression of the c-erbB-2 oncoprotein was poorly associated with EGFR expression and the conventional pathologic features, and it was weakly associated with DNA ploidy and nodal status. Univariate analysis showed that c-erbB-2 expression, nodal status, DNA ploidy, and EGFR provided significant prognostic information concerning 4-year relapse-free survival (RFS) with the odds ratios (ORs) of not relapsing of 2.94, 2.83, 2.34, and 2.20, respectively. Regarding overall survival (OS) at 4 years, only nodal status and DNA ploidy had prognostic significance, with the ORs of not dying of 2.68 and 2.80, respectively. Applying multivariate analysis to RFS, 21N when adjusted for nodal status, EGFR, and DNA ploidy (full model) failed to retain prognostic value (P = .202), whereas nodal status was the most significant indicator of relapse (P = .027) followed by DNA ploidy (P = .056) and EGFR (P = .093). CONCLUSIONS: This study suggests that overexpression of the c-erbB-2 oncoprotein appears to be an important indicator of relapse in stage I-II breast cancer when singly evaluated. Multivariate analysis shows that the determination both of nodal status and DNA ploidy improves our ability to identify subsets of patients with different prognoses, and allows for a better selection of patients for systemic adjuvant treatments.

Multivariate-analysis of prognostic factors in 232 patients with clinical stage-I endometrial adenocarcinoma using the new figo surgical staging system.

A retrospective analysis is reported in 232 patients with clinical Stage I endometrial adenocarcinoma diagnosed between 1980 and 1988, treated with combined surgery and adjuvant irradiation. Tumors were restaged according to the FIGO (1988) surgical staging system (SSS) in order to assess the prognostic value of this revised classification and of the conventional clinico-pathological features (age, performance status, grade and depth of myometrial invasion). The 5-year relapse-free survival (RFS) and overall survival (OS) of the series was 85% and 90.8%, respectively. Both 5-year RFS and OS were not significantly different adopting the FIGO (1971) clinical Stage (Stage IA 93% and 88% vs Stage IB 88.5 and 82%. respectively) whereas they were significant by FIGO SSS (Stage IA 96% and 93% vs Stage IB 94% and 88.5% vs Stage IC 74% and 63%, respectively) (p=0.001 and p=0.0005, respectively). Other factors that significantly affected 5-year RFS or OS at univariate analysis were age (p=0.01 and p<0.0001, respectively), performance status (p=0.035 and p=0.001, respectively), grade (p=0.015 and p<0.0001, respectively) and myometrial invasion (p=0.0017 and p=0.0003, respectively). A multivariate analysis of these prognostic variables showed that FIGO SSS was the only significant and independent (p=0.01) indicator for recurrence. However, when therapy was added to the model, FIGO SSS failed to retain significance (p=0.11). Concerning OS age (p<0.0001), performance status (p=0.04) and FIGO SSS (p=0.05) were significant and independent prognosticators, also when therapy was included in the analysis. In conclusion, this study shows that the new FIGO SSS is a useful prognosticator as well as is age and performance status, in early Stage endometrial adenocarcinoma.

Primary radiotherapy versus surgery and radiotherapy in the management of postmenopausal locally advanced breast cancer.

From 1978 through 1984, 103 postmenopausal patients with locally advanced breast cancer (T4 N1-2-3 MO) were treated by definitive radiotherapy (XRT, 35 patients) or mastectomy and postoperative radiotherapy (RM + XRT, 68 patients). A control group of 35 of the 68 RM + XRT patients was selected by matching several prognostic variables with the XRT group. Patients were followed for 4 to 10 years. At 5 years the probabilities of overall survival and relapse-free survival were 49.9% and 33.2% for XRT patients and 49.2% and 42.8% for RM + XRT patients, respectively (with no significant difference). The probability to remain free of local-regional progression at 5 years, with censoring of deaths, was 71.9% in the XRT group and 79.8% in the RM + XRT group. Of the patients treated with definitive radiotherapy, those who received 60 Gy or more to the primary tumor had a significantly better 5-year rate of local control: 88.0% vs. 68.0%, p less than 0.05. Our results suggest that adequate doses of radiotherapy can provide long-term local-regional control in a large proportion of survivors and can spare mastectomy in most patients, without however achieving substantial improvements in the poor survival results.

[Breast carcinoma. Technical problems of radiotherapy. Proposal of an algorithm as an alternative to the lack of scintigraphic visualization of the internal mammary lymph nodes]. / Carcinoma mammario. Problemi di tecnica radioterapica. Proposta di un algoritmo in alternativa alla non visualizzazione scintigrafica delle catene mammarie interne.

In early breast cancer, radiation therapy following conservative surgery needs a topographic evaluation of internal mammary lymph nodes. Three-dimensional lymphoscintigraphy (IML3D) is an useful method for this purpose. The average depth of the lymph nodes is closely correlated with the square root of the body weight/height ratio. We calculated the individual maximum depth of the lymph nodes from this function; the parameter was then verified with the experimental data from our series of cases (53 patients). Although the suggested algorithm needs to be verified on a larger number of patients, we believe the empirical maximum depth measurement to be useful when IML3D is unfeasible or the internal mammary lymph nodes are not demonstrated on scintigraphic scans.