Second Primary Tumors In Patients Research Articles

18F‐FDG‐PET/CT versus panendoscopy for the detection of synchronous second primary tumors in patients with head and neck squamous cell carcinoma

This study assesses the additional value of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography/CT ((18)F-FDG-PET/CT) with respect to synchronous primaries in patients undergoing panendoscopy for staging of head and neck squamous cell carcinoma. In all, 311 patients underwent both modalities. Cytology, histology, and/or clinical/imaging follow-up served as reference standard. The prevalence of second primary tumors detected by panendoscopy was 4.5%, compared with 6.1% detected by (18)F-FDG-PET/CT. The sensitivity for panendoscopy was 74%, the specificity was 99.7%, the positive predictive value (PPV) was 93%, and the negative predictive value (NPV) was 98%. The sensitivity for (18)F-FDG-PET/CT was 100%, the specificity was 95.7%, the PPV was 59%, and the NPV was 100%. (18)F-FDG-PET/CT is superior to panendoscopy. With a negative (18)F-FDG-PET/CT, the extent of endoscopy can be reduced to the area of the primary tumor. Due to the costs, (18)F-FDG-PET/CT is recommended only in advanced disease to assess potential distant disease. In early-stage cancer, panendoscopy is accurate enough to rule out secondary tumors.

FDG-PET and detection of distant metastases and simultaneous tumors in head and neck squamous cell carcinoma: A comparison with chest radiography and chest CT

Detection of distant metastases and second primary tumors in patients with head and neck squamous cell carcinoma (HNSCC) is of importance because of the impact on treatment and prognosis. The aim of this study was to assess the value of whole-body fluorodeoxyglucose-positron emission tomography (FDG-PET) in detecting distant metastases and second primary tumors below clavicular level in HNSCC compared to chest CT and chest radiography (CXR). Patient records of 149 consecutive patients with a primary HNSCC in whom a whole-body FDG-PET for initial staging was performed were reviewed. FDG-PET showed a sensitivity and specificity for detecting distant disease of 92% and 93%, respectively. Chest CT (n=82) showed a sensitivity and a specificity of 74% and 61% respectively. CXR (n=106) showed a sensitivity and a specificity of 41% and 91%, respectively. FDG-PET was shown to be able to detect distant metastases and second primary tumors in HNSCC with a high sensitivity and specificity. The higher sensitivity of PET compared to chest CT is mainly due to the detection of extrapulmonary malignancy. Sensitivity of PET and CT were similar in detecting intrapulmonary malignancy, but PET specificity was significantly higher. FDG-PET helps to determine the nature of pulmonary lesions and might be considered as a first diagnostic modality for detecting distant disease in advanced HNSCC.

Distant metastases and synchronous second primary tumors in patients with newly diagnosed oropharyngeal and hypopharyngeal carcinomas: evaluation of 18F-FDG PET and extended-field multi-detector row CT

Patients with oropharyngeal or hypopharyngeal squamous cell carcinoma (SCC) have a high risk of having distant metastases or second primary tumors. We prospectively evaluate the clinical usefulness of (18)F-fluoro-2-deoxyglucose positron emission tomography ((18)F-FDG PET), extended-field multi-detector computed tomography (MDCT), and their side-by-side visual correlation for the detection of distant malignancies in these two tumors at presentation. A total of 160 patients with SCC of the oropharynx (n = 74) or hypopharynx (n = 86) underwent (18)F-FDG PET and extended-field MDCT to detect distant metastases or second primary tumors. Suspected lesions were investigated by means of biopsy, clinical, or imaging follow-up. Twenty-six (16.3%) of our 160 patients were found to have distant malignancy. Diagnostic yields of (18)F-FDG PET and MDCT were 12.5% and 8.1%, respectively. The sensitivity of (18)F-FDG PET for detection of distant malignancies was 1.5-fold higher than that of MDCT (76.9% vs. 50.0%, P = 0.039), while its specificity was slightly lower (94.0% vs. 97.8%, P = 0.125). Side-by-side visual correlation of MDCT and (18)F-FDG PET improved the sensitivity and specificity up to 80.8% and 98.5%, respectively, leading to alteration of treatment in 13.1% of patients. A significant difference in survival rates between its positive and negative results was observed. (18)F-FDG PET and extended-field MDCT had acceptable diagnostic yields for detection of distant malignancies in untreated oropharyngeal and hypopharyngeal SCC. (18)F-FDG PET was 1.5-fold more sensitive than MDCT, but had more false-positive findings. Their visual correlation improved the diagnostic accuracy, treatment planning, and prognosis prediction.

Use of 18F-Fluorodeoxyglucose Positron Emission Tomography in Patients with Rare Head and Neck Cancers

ObjectivesThe clinical utility of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been demonstrated in major head and neck cancers (HNCs) but is unclear in rare HNCs. We therefore evaluated FDG PET in the management of patients with rare HNCs.MethodsFDG PET and CT/MRI scanning were performed at the initial staging and/or the follow-up in 24 patients with rare HNCs, 10 with melanoma, 9 with sarcoma, 3 with olfactory neuroblastomas, and 2 with basal cell carcinoma. The diagnostic accuracy of CT and FDG PET for detecting primary tumors and metastases were compared with a histopathologic reference. The association between the PET results and the clinicopathologic parameters predicting tumor invasion, histologic grade and disease-free survival (DFS), was assessed.ResultsThe overall accuracies of FDG PET and CT/MRI were 92% and 79%, respectively, for detecting primary tumors and 91% and 74%, respectively, for nodal metastases, but the differences were not significant due to the small number of patients. The sensitivity and specificity of FDG PET for detecting distant metastases and second primary tumors were 100% and 87%, respectively. Follow-up FDG PET correctly diagnosed locoregional recurrence in all 12 patients, as shown by biopsy, and distant metastases in 6 patients. However, thickness of melanoma, histologic grade of sarcoma, and DFS were not associated with tumor FDG uptake.ConclusionFDG PET may be useful for staging, posttreatment monitoring, and detection of distant metastases and second primary tumors in patients with rare HNCs.

‘Increased incidence of secondary tumours in thyroid cancer patients’: a fact or a sophism?

In the paper by Robbert B T Verkooijen et al. (1), they described an increased incidence of second primary tumours (SPTs) in thyroid cancer patients. They found no association with iodine-131 (I-131) treatment of differentiated thyroid cancer (DTC), but surmised a common aetiology and/or genetic mechanism causing the observed increased prevalence of SPTs, especially breast cancer, in thyroid cancer patients. In concluding, they recommended close clinical follow-up for early diagnosis of SPTs in patients with DTC. The astonishing results and conclusions of Verkooijen et al. prompted us to search our own database; it contained 1087 patients (73% females, 27% males) with the diagnosis of thyroid cancer. The follow-up period ranged between a minimum of 1 year and a maximum of 30 years (mean 7G5 years); the mean age of the patients was 51G16 years and 103 patients had passed away. Therapeutic doses of I-131 had been given to 933 patients, and 154 had very small primary lesions of DTC with a very low risk of tumour recurrence, and therefore received no I-131 therapy. We included patients with medullary carcinoma in our analysis, in contrast to Verkooijen et al., but otherwise age, gender distribution, histopathology, ablation doses and time points of treatment were comparable with the group reported by Verkooijen et al. In our group, we found 125 additional SPTs in 112 patients (11 patients had three tumours, 1 patient had four tumours), yielding a percentage of 11.5% vs 14.2% (40 out of 282 patients). Fifty-five tumours had occurred several years prior to the diagnosis of DTC (mean 8.4 years). Thus, our data analysis ultimately revealed 5% of patients who had developed an SPT (following the diagnosis of DTC and treatment) when compared with 7% of those reported by Verkooijen et al. These data are in accordance with others, such as Bhattacharyya et al. and Canchola et al. (2, 3). Verkooijen et al. reported a significantly increased standardized incidence ratio (SIR 3.95) for SPTs only when patients with breast cancer before thyroid cancer were included; their SIR for SPTs following DTC overall was 1.13, which is nearly the same as our value of 1.06. Sadetzki et al. (4) found an elevated risk in women with breast cancers for DTCs. Cengiz et al. (5) also observed

M08-04: Retinoids and rexinoids in lung cancer biology and therapy

Retinoids are natural or synthetic vitamin A derivatives that have long been implicated in an important role in cancer biology and prevention. Studies show that vitamin A deprivation can lead to an increased carcinogenesis in the lung and upper aerodigestive tract. Early trials by Hong et al of a high dose synthetic retinoid, isotretinoin, showed that this agent could reverse early to intermediate head and neck premalignancy, and that high doses of isotretinoin given for one year in 8 patients treated definitively for an advanced head and neck primary tumors prevented second primary tumors (SPTs) for a period of two to three years after cessation of retinoid therapy. However, high doses of isotretinoin were intolerable to most patients, and a larger randomized trial of isotretinoin in head and neck squamous cell cancer failed to reproduce the earlier data, with no evidence of reduction in SPTs. Moreover, this agent was ineffective at tolerable doses in preventing SPTs in patients treated for early stage non-small cell lung cancer (NSCLC). Both retinoids and rexinoids, and in fact, all synthetic vitamin A compounds function by binding to cograte retinoid nuclear receptors, the retinoic acid receptors (RARs), and retinoid X receptors (RXRs). Synthetic rexinoids were first synthesized in the early 1990s, given the diverse binding partners (RAR/RXR or LXR/RXR heterodimers, for example or RXR/RXR homodimers) that these compounds can bind to. The rexinoid, bexarotene, was introduced into clinical trials in the early 1990s and was shown to produce prolonged stabilization in patients with NSCLC. Subsequent combinations with standard front line chemotherapy for NSCLC appeared promising with longer than expected median survivals in the absence of more pronounced responses. Two phase III trials of bexarotene with front line chemotherapy failed to show superiority over the standard chemotherapy arms. However, in those patients who had grade 3 hypertriglyceridemia due to bexarotene, median survival appeared to be meaningfully better than in those patients treated with chemotherapy alone. The biological mechanisms underpinning these surprising results are unclear at this time and are currently under investigation. Given the broad biological effects of rexinoids and retinoids, continued investigation of these agents in lung and aerodigestive tract cancers is imperative for the advancement of this important class of differentiating agents.

P214 Lugol cromoscopy for early diagnosis of second primary tumors in patients treated for carcinoma of the head and neck

P214 Lugol cromoscopy for early diagnosis of second primary tumors in patients treated for carcinoma of the head and neck

The incidence of second primary tumors in thyroid cancer patients is increased, but not related to treatment of thyroid cancer

The aim of the present study is to assess the prevalence of second primary tumors in patients treated for thyroid cancer. Furthermore, we wanted to assess the standardized risk rates for all second primary tumors, but especially for breast cancer, as data in the literature indicate an excessive risk in differentiated thyroid cancer (DTC) patients for this tumor. We included consecutive patients, who received ablation treatment with I-131 at the Leiden University Medical Center between January 1985 and December 1999 (n = 282). The mean period of follow-up was 10.6 +/- 4.1 years. Thirty-five of the 282 patients (12.4%) had a second primary tumor (SPT), either preceding or following the diagnosis of thyroid cancer. Five other patients had three primary tumors, including DTC. As a result, 40 additional tumors were found in this group, revealing an overall prevalence of 14.2%. Twenty tumors (7.1%) preceded the thyroid cancer with a mean interval of 5.7 years (range: 0.5-22.0 years), whereas 20 tumors (7.1%) occurred after this tumor with a mean interval of 6.7 years (range: 1.0-15.0 years). In 13 female patients, breast cancer was found as SPT. The standardized incidence rate (SIR) for all cancers after the diagnosis of DTC in this study population was not increased (1.13; confidence interval (CI): 0.68-1.69). However, we found an increased SIR of 2.26 (CI: 1.60-3.03) for all cancers either following or preceding DTC, which is mainly caused by a SIR of 3.95 (CI: 2.06-6.45) for breast cancer. Patients with DTC have an overall increased standardized incidence rate for second primary tumors, but not for second primary tumors following I-131 therapy. These findings suggest a common etiologic and/or genetic mechanism instead of a causal relation.

The risk of second primary tumors in patients with nasopharyngeal carcinoma after definitive radiotherapy

Second primary tumors (SPTs) have a substantial impact on survival in cancer patients. However, risk factors for SPTs have not been documented well, especially in nasopharyngeal carcinoma (NPC). The objective of this retrospective analysis was to evaluate such risks in patients with NPC after they received definitive radiation treatment. Three hundred twenty-six consecutive patients with pathologically confirmed, nonmetastatic, undifferentiated NPC who received treatment between January 1, 1994 and December 30, 1995 were analyzed. All patients were restaged in accordance with the 2002 American Joint Committee on Cancer staging classification. There were 18 patients (5.5%) with Stage I NPC, 152 patients (46.6%) with Stage II NPC, 101 patients (31.0%) with Stage III NPC, and 55 patients (16.9%) with Stage IVA or IVB NPC at initial diagnosis. All patients received definitive radiotherapy with either Cobalt-60 or megavoltage therapy. High-dose-rate brachytherapy was given to 23 patients either as part of their primary treatment or as adjuvant treatment for residual lesions. The median follow-up for all patients was 5.6 years (range, 1.0-8.0 years). Seventeen patients (5.2%) developed SPTs, for an average annual rate of 1.0%, and the 5-year cumulative incidence was 5.8%. Six SPTs were located within the radiation field. The cumulative incidence of in-field SPTs was 0.35% at 3 years and 1.2% at 5 years, and the average annual rate was 0.35%. Eleven patients (64.7%) had tumors of the upper aerodigestive tract (UADT). Among the 14 SPTs that occurred within 5 years after radiotherapy, only 3 tumors (21.4%) occurred within the radiation field. In contrast, all 3 SPTs that occurred >5 years after radiotherapy occurred within the radiation field (P = .029). Multivariate analysis showed that age was the only independent risk factor for developing SPTs after RT for NPC. Advanced age (age >or=50 years) was associated with a 37% increased risk of developing SPTs (relative risk, 1.367; 95% confidence interval, 1.067-1.1753; P = .014). Other factors, including gender, tumor or lymph node classification, chemotherapy, total radiation dose to the nasopharynx, reirradiation, and adjuvant brachytherapy did not influence the risk of SPTs. SPTs in patients with NPC occurred preferentially in the UADT and tended to develop within the irradiated field >5 years after patients received radiation. Older patients with NPC (age >or=50 years) may be at increased risk. Further studies with larger samples and longer follow-up will be needed to confirm these findings.

P.204 Second primary tumours in patients with head and neck cancers

Background: Nevoid basal cell carcinoma syndrome (NBCC) is an autosomal dominant multisystem disorder. Persons with the NBCC gene have varied susceptibility to basal cell carcinoma (BCC) development.Objective: We examined the anatomic site-specific distribution of BCCs and the relation between sun exposure and numbers of BCCs in NBCC cases.Methods: A questionnaire asking about lifetime sun exposure, sun behavior habits, and number of BCCs was sent to 16 families with NBCC evaluated between 1985 and 1991. The results were compared with previously published data for the general population.Results: In the general population, 88% of all BCCs in women and 86% in men occurred on the face, head, neck, and arms versus 59% in women with NBCC and 65% in men with NBCC. Of BCCs in the general population 9% and 12% occurred on the trunk versus 38% and 32% of BCCs in NBCC cases, in women and men, respectively. We did not observe a strong relation between numbers of BCCs and history of lifetime sun exposure.Conclusion: The anatomic-site distribution of BCCs suggests that frequent sun exposure may not be essential for the development of BCCs in patients with NBCC. However, the observation that there are more tumors on sun-exposed areas suggests that exposure to the sun promotes the development of BCCs in patients with NBCC.

Multiple primary malignancies (MPM) in Israeli patients with soft tissue sarcomas (STS)

9571 Background: An increased incidence of MPM has been reported in association with STS. In a previous series we reported 28 patients out of 375 patients with STS as having second or third additional primary malignancies not all accountable by previous chemotherapy or radiotherapy. In the present series we re-examined the phenomenon in a large Israeli database of adult STS patients. Methods: A retrospective search of the database of approx.1350 adult STS patients who were referred, diagnosed or treated at our center between 1995–2005. Results: A group of 132 patients (F=66, M=66, age 1–87y, median 59y) with STS and at least one additional malignancy was retrieved. Overall, a family history of malignancy was reported by 26%, exposure to carcinogens prior to 1st tumor by 10%. Exposure to carcinogens/RT/Chemo given for the 1st tumor prior to the 2nd tumor was recorded in 61%. Taken together (n=132), STS were associated with a second malignancy arising mainly from the various sites of the urogenital system (18%), breast (17%), GIT (11%), lung (8%), and thyroid (7%). When non-STS was the first malignancy (n=73 at a median age 59y), the main malignancies included breast (23% ), colorectal (11%), melanoma (10%), prostate (8%), thyroid (7%), and bladder (5%). STS as a second primary (n=66) after a median time of 8y, included MFH (28%), LMS (16%), and liposarcoma (15%). The STS originated in a limb in 42%, trunk- 12%, retroperitoneum or viscera-34%, and unknown origin-1%. In the other 6 patients (median age 76.5), STS was the 3rd or more primary tumor. When STS was the first malignancy (n=59 at a median age of 59y), the second primary cancers were diagnosed after a median of 5 years, and included lung (15%), STS of different type (12%), kidney (10%), skin (10%), breast (10%), colorectal (8.5%), prostate (8.5%), and thyroid (7%). Updated survival data will be presented. Conclusions: The incidence of malignancies among patient population of primary STS is higher than the incidence of the same malignancies in the general population. This implies for the need to search for an occult second primary tumor in patients with STS as an integral part of their follow-up. No significant financial relationships to disclose.

Evaluation of glutathione S‐transferase polymorphisms and mutagen sensitivity as risk factors for the development of second primary tumors in patients previously diagnosed with early‐stage head and neck cancer

The objective of this study was to evaluate the effects of polymorphisms in 2 genes in the glutathione S-transferase (GST) family and the mutagen-sensitivity phenotype on the risk of second primary tumors (SPTs) in patients with previously diagnosed early-stage head and neck squamous cell carcinoma. Data were available for 303 patients who were enrolled in a placebo-controlled chemoprevention trial of low-dose 13-cis-retinoic acid to reduce the occurrence of SPTs. A Cox proportional hazards model and survival tree analysis were used to evaluate the association between specified genetic variations and the development of SPTs. The average number of bleomycin-induced chromatid breaks per cell was used to quantify mutagen sensitivity as an individual patient's degree of sensitivity to genotoxicity. The GST-M1 null genotype was associated with an increased risk for any SPTs (hazard ratio [HR], 1.99; 95% confidence interval [95% CI], 1.11-3.56) and for tobacco-related SPTs (HR, 2.16; 95% CI, 1.01-4.62) after adjusting for covariates. The GST-T1 null genotype and bleomycin-induced chromatid breaks were not associated with a statistically significant increased risk for SPTs or tobacco-related SPTs after similar adjustment. Simultaneous nonnull status for both GST genotypes was associated with a decreased risk for any SPTs (HR, 0.52; 95% CI, 0.28-0.96) and tobacco-related SPTs (HR, 0.50; 95% CI, 0.22-1.11) compared with null status for GST-M1 accompanied by nonnull status for GST-T1. An association was observed between the development of SPTs and the GST-M1 null genotype after successful treatment for early-stage head and neck squamous cell carcinoma. The GST-T1 null genotype and bleomycin-induced chromatid breaks were not associated with an increased risk, and no significant interactions were identified.

Pulmonary Squamous Cell Carcinoma following Head and Neck Squamous Cell Carcinoma: Metastasis or Second Primary?

To distinguish a metastasis from a second primary tumor in patients with a history of head and neck squamous cell carcinoma and subsequent pulmonary squamous cell carcinoma. For 44 patients with a primary squamous cell carcinoma of the head and neck followed by a squamous cell carcinoma of the lung, clinical data, histology, and analysis of loss of heterozygosity (LOH) were used to differentiate metastases from second primary tumors. Clinical evaluation suggested 38 patients with metastases and 6 with second primaries. We developed a novel interpretation strategy based on biological insight and on our observation that multiple LOH on different chromosome arms are not independent. LOH analysis indicated metastatic disease in 19 cases and second primary squamous cell carcinoma in 24 cases. In one case, LOH analysis was inconclusive. For 25 patients, LOH supported the clinical scoring, and in 18 cases, it did not. These 18 discordant cases were all considered to be second primary tumors by LOH analysis. A considerable number of squamous cell lung lesions (50% in this study), clinically interpreted as metastases, are suggested to be second primaries by LOH analysis. For these patients, a surgical approach with curative intent may be justified.

Second Primary Tumors Involving Non-small Cell Lung Cancer: Prevalence and Its Influence on Survival

Objectives Patients with lung cancer have a relative high risk for second primary cancers. We studied the prevalence of second primary tumors in patients with a diagnosis of non-small cell lung cancer (NSCLC) in their history or at follow-up. Furthermore, we studied survival in subgroups of those patients Methods and patients Retrospectively, 860 patients with NSCLC that had been diagnosed in the period from January 1, 1990, to December 31, 1999, were evaluated for second primary cancers either in their history or in the follow-up period. The patients were divided into the following four groups: group I, patients with another primary tumor detected in the follow-up period (n = 44); group II, patients with another primary tumor in their history (n = 148); group III, patients with no other primary tumor found in their history or at follow-up (n = 634); and group IV, patients with more than one other primary tumor in found in their history or at follow-up (n = 34) Results The most frequently diagnosed double tumors were located in the lungs, the head and neck region, and the urinary tract. The interval between another malignancy as the first tumor (group II, 83 months) and NSCLC as the second malignancy was significantly longer than vice versa (group I, 14.5 months; p < 0.05). In > 80% of patients, the second primary tumors were diagnosed within 1 year after NSCLC was diagnosed. The 5-year survival rate is significantly better for patients with more than two primary malignancies compared to patients without two primary malignancies and patients with one other tumor in their history (p = 0.004 and 0.012, respectively). The 5-year survival rate in patients with a second tumor in the follow-up period was better than in patients without any other second tumor (p = 0.029). As the TNM stage and therapy were comparable in all subgroups, it could not be used as explanation for the difference in survival rates Conclusion In 25% of patients, additional tumors that were NSCLC were diagnosed either in their history or in the follow-up period. The majority of second tumors following NSCLC are diagnosed within 1 year. Nevertheless, patients with a second tumor tend to have an overall better survival rate than patients without second primaries, suggesting different growth habits Patients with lung cancer have a relative high risk for second primary cancers. We studied the prevalence of second primary tumors in patients with a diagnosis of non-small cell lung cancer (NSCLC) in their history or at follow-up. Furthermore, we studied survival in subgroups of those patients Retrospectively, 860 patients with NSCLC that had been diagnosed in the period from January 1, 1990, to December 31, 1999, were evaluated for second primary cancers either in their history or in the follow-up period. The patients were divided into the following four groups: group I, patients with another primary tumor detected in the follow-up period (n = 44); group II, patients with another primary tumor in their history (n = 148); group III, patients with no other primary tumor found in their history or at follow-up (n = 634); and group IV, patients with more than one other primary tumor in found in their history or at follow-up (n = 34) The most frequently diagnosed double tumors were located in the lungs, the head and neck region, and the urinary tract. The interval between another malignancy as the first tumor (group II, 83 months) and NSCLC as the second malignancy was significantly longer than vice versa (group I, 14.5 months; p < 0.05). In > 80% of patients, the second primary tumors were diagnosed within 1 year after NSCLC was diagnosed. The 5-year survival rate is significantly better for patients with more than two primary malignancies compared to patients without two primary malignancies and patients with one other tumor in their history (p = 0.004 and 0.012, respectively). The 5-year survival rate in patients with a second tumor in the follow-up period was better than in patients without any other second tumor (p = 0.029). As the TNM stage and therapy were comparable in all subgroups, it could not be used as explanation for the difference in survival rates In 25% of patients, additional tumors that were NSCLC were diagnosed either in their history or in the follow-up period. The majority of second tumors following NSCLC are diagnosed within 1 year. Nevertheless, patients with a second tumor tend to have an overall better survival rate than patients without second primaries, suggesting different growth habits

Second Primary Tumors Involving Non-small Cell Lung Cancer*

Patients with lung cancer have a relative high risk for second primary cancers. We studied the prevalence of second primary tumors in patients with a diagnosis of non-small cell lung cancer (NSCLC) in their history or at follow-up. Furthermore, we studied survival in subgroups of those patients. Retrospectively, 860 patients with NSCLC that had been diagnosed in the period from January 1, 1990, to December 31, 1999, were evaluated for second primary cancers either in their history or in the follow-up period. The patients were divided into the following four groups: group I, patients with another primary tumor detected in the follow-up period (n = 44); group II, patients with another primary tumor in their history (n = 148); group III, patients with no other primary tumor found in their history or at follow-up (n = 634); and group IV, patients with more than one other primary tumor in found in their history or at follow-up (n = 34). The most frequently diagnosed double tumors were located in the lungs, the head and neck region, and the urinary tract. The interval between another malignancy as the first tumor (group II, 83 months) and NSCLC as the second malignancy was significantly longer than vice versa (group I, 14.5 months; p < 0.05). In > 80% of patients, the second primary tumors were diagnosed within 1 year after NSCLC was diagnosed. The 5-year survival rate is significantly better for patients with more than two primary malignancies compared to patients without two primary malignancies and patients with one other tumor in their history (p = 0.004 and 0.012, respectively). The 5-year survival rate in patients with a second tumor in the follow-up period was better than in patients without any other second tumor (p = 0.029). As the TNM stage and therapy were comparable in all subgroups, it could not be used as explanation for the difference in survival rates. In 25% of patients, additional tumors that were NSCLC were diagnosed either in their history or in the follow-up period. The majority of second tumors following NSCLC are diagnosed within 1 year. Nevertheless, patients with a second tumor tend to have an overall better survival rate than patients without second primaries, suggesting different growth habits.

13-cis retinoic acid in head and neck cancer chemoprevention: results of a randomized trial from the Italian Head and Neck Chemoprevention Study Group

Patients with squamous cell carcinoma of the head and neck (HNSCC) after being treated radically remain at high risk for both recurrent and second primary tumours. 13-cis retinoic acid (13-cRA) was demonstrated to reverse pre-malignant lesions of the oral cavity and to reduce the incidence of second primary tumours in patients treated radically for HNSCC. Synergism between retinoids and interferon in tumoural cell lines have been demonstrated. Based on these data, the Italian Head and Neck Chemoprevention Study Group started a randomized chemoprevention study in patients radically treated for stage III and IV HNSCC. From February 1992 to January 1996, 267 patients were randomized: 126 were allocated to the control group, 126 were randomized to receive 13-cRA at a dose of 0.5 mg/kg per day per os and 15 patients have been assigned to the group of 13-cRA plus interferon alpha2a (IFN-alpha2a) at a dose of 3,000,000 UI 3 times a week (randomization in this arm interrupted due to administrative financial problems). The mean follow-up was 39 months. The 5-year actuarial survival was 58.9% for patients of the 13-cRA group and 57.2% for those of the control group (P=0.94). Among evaluable patients, disease progression was observed in 45 of 123 patients (36.6%) of the 13-cRA group and in 42 of 124 (33.9%) of the control group. The 5-year actuarial relapse-free survival was 48.9% for the 13-cRA group and 55.6% for the control group (P=0.62). Adverse effects, mostly of grade I were reported in 69.4% of treated patients (haematologic disorders, mucositis, conjunctivitis, cutaneous toxicity, hypertriglyceridemia and hypercholesterolemia). Only 5 patients (4.1%) reported grade III-IV toxicity. Low-dose of 13-cRA given for 1 year is ineffective as chemoprevention in patients with radically treated HNSCC.

Competing causes of death and second primary tumors in patients with locoregionally advanced head and neck cancer treated with chemoradiotherapy.

The purpose of this retrospective analysis was to evaluate the emergence of second primary malignancies and the contribution of different causes of death to the outcome of patients with locoregionally advanced head and cancer receiving primary chemoradiotherapy. We studied 324 patients with stage IV squamous cell head and neck cancer who were enrolled on five consecutive multicenter Phase II studies of concurrent chemoradiotherapy. All of the regimens included concurrent 5-fluorouracil and hydroxyurea on an alternate week schedule with radiotherapy, either alone (FHX) or with cisplatin (C-FHX) or paclitaxel (T-FHX). The cumulative incidence of second primary tumors or death from any cause was estimated using methods of competing risk analysis. Median follow-up of surviving patients was 5.2 years (2-10.6 years). The 5-year overall survival and progression-free survival of the cohort were 46% and 65%, respectively. Causes of death and median time of occurrence were as follows: disease (n = 88; 1.5 years), treatment-associated acute or late complications (n = 30; 4 months), second primary tumors (n = 18; 3.5 years), comorbidities (n = 41; 1.9 years), and unknown (n = 20; 5.1 years). Predominant causes of death from comorbidities were cardiac and respiratory illnesses. Twenty-six patients (8%) developed a second primary tumor at a median time of 2.8 years (4 months to 10 years). The cumulative incidence of second primary tumors was 5%, 7%, and 13% at 3, 5, and 10 years, respectively. The most frequent site of second primaries was the lung (n = 13), followed by the esophagus (n = 3) and head and neck (n = 2) Patients with locoregionally advanced head and neck cancer treated with concurrent chemoradiotherapy are potentially curable but face significant risks of mortality from causes other than disease progression. Ameliorating toxicity, and implementing secondary screening and chemoprevention strategies are major goals in the management of head and neck cancer.

A second primary tumor in a patient with retinoma

Aim: To evaluate the frequency of the co-occurrence of a retinoma and another primary tumor. Method: Presentation of a case report and review of the literature. Results: A cutaneous melanoma was observed in a 52-year-old man, who was known to have two retinomas in the right eye. Five other cases were found in a review of the literature, suggesting the possibility of an increased risk of developing a second primary tumor in patients with retinoma. The occurrence of cutaneous melanoma as a second primary tumor after retinoma and/or retinoblastoma is discussed. Conclusion: There might be an increased risk for patients with retinoma to develop another primary tumor, necessitating regular follow-up of these patients.

Correlação entre a evolução clínica e a freqüência de micronúcleos em células de pacientes portadores de carcinomas orais e da orofaringe

To verify the correlation between the micronucleus frequency and the presence of local recurrences or second primary lesion in patients with carcinoma of the oral cavity. We studied the frequency of micronucleus of the oral mucosa in 27 untreated patients with carcinoma of the oral cavity and oropharynx. The patients were monthly followed after initial treatment, in an attempt to identify local recurrences or second primary lesions. Of the 24 patients evaluated during the whole time, 5 cases (20,8%) were alive and free of disease, and 19 cases died, 18 (75%) owing to cancer and 1 to perfurative peptic ulcer. In relation to micronucleus frequency, no difference was observed among the patients with local recurrence of the disease (N=14) and the patients who died of other causes or were alive and free of disease (N=10) (p = 0.83). There was higher micronucleus frequency in the stages T3 and T4 (p = 0.01). In the present study was not possible to find a clinical correlation between the frequency of micronucleus of the oral mucosal and the risk of development of local recurrence or second primary tumor in patients with upper aerodigestive tract carcinoma.

Anticancer activity and mechanism of action of retinoids in oral and pharyngeal cancer

Retinoids are the natural and synthetic derivatives of vitamin A. Epidemiological studies indicate that a low intake of vitamin A is associated with an increased risk of squamous cancer. In vitro studies on cancer cells show that exposure to retinoids results in the inhibition of growth, by blocking the cell cycle or by inducing apoptosis. With respect to the clinical efficacy of retinoids some positive effects have been observed in early stage oral and oropharyngeal cancer. Administration of retinoids has been shown to elicit responses in leukoplakia, a premalignant lesion of the oral mucosa that frequently develops into invasive cancer. Furthermore, it has been possible with a retinoid, 13-cis-retinoic acid, to delay or inhibit the development of second primary tumors in patients who have been curatively treated for a first primary tumor in the oral cavity or oropharynx. Recent trials, however, failed to show protective effects on the development of second primary tumors. Because of the short duration of the response, the intrinsic resistance to retinoids and the toxic side effects, the treatment with this class of compounds has not become a standard therapy. Recent studies have shed light on how preneoplastic and neoplastic cells defend themselves against the growth inhibiting action of retinoids. An increased retinoid breakdown and an inactivation of nuclear retinoid receptor appear to be the cause of acquired or intrinsic resistance. This knowledge can be used to develop novel tumor-selective strategies. This review gives an update on the role of retinoids in oral and oropharyngeal cancer and their precursor lesions. The focus will be on the anticancer activity, the mechanism of action and future directions.