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Background: The cancer burden in Israel is substantial. Recently calculated population attributable fractions (PAFs) for modifiable cancer risk factors in the US and the UK have indicated much room for prevention. Our aim was to estimate PAFs for selected modifiable cancer risk factors in Israel. Methods: Exposure data on selected modifiable risk factors were based on national health surveys conducted in 2013–2015. Data on invasive cancer incidence in 2015 were retrieved from the Israel National Cancer Registry (INCR). Relative risks (RRs) for specific cancer sites were retrieved from the scientific literature. PAFs were calculated for selected modifiable risk factors using an approximate formula. Results: In 2015, 21% of all invasive cancer cases in Israel were attributed to smoking, 9% to excess body weight, and 1.5% to alcohol intake. Moreover, 32% of all invasive cancer cases were attributed to all modifiable risk factors (combined) included in our study. Conclusions: Quantifying the contribution of modifiable risk factors to the incidence of certain cancer types in Israel offers an opportunity for primary prevention and enables informed decision-making with respect to the prioritization of interventions.

Objectives The Prevalence Incidence Analysis Model method is used for predicting disease prevalence, using past data on incidence and relative survival. Our objective was to propose and evaluate a modified approach for choosing the Prevalence Incidence Analysis Model. Study Design and Setting Instead of the standard approach using the likelihood ratio statistic, we find the model that predicts most successfully the prevalence in the last available Y years using data up to but not including those Y years and then use that model to predict future prevalence another Y years ahead using all the data. We also make an “alignment” adjustment using the last known prevalence level. We evaluate the relative performance of the modified and standard methods using data on cancer from Israel in 1983–2013. Results In this example, the modified approach gave as good or better predictions than the standard. Using the modified approach, we forecast cancer prevalence in Israel for 2014–2024 to increase at a gradually accelerating rate from the current 10,000 per year to 12,000 per year by 2020, reaching a total of 380,000 by 2024. Conclusion The modified approach may offer improved forecasting, but further methodological work on forecasting cancer prevalence is needed.

The number of cancer survivors has been increasing worldwide and is now approximately 32.6 million and growing. Cancer survivors present a challenge to health care providers because of their higher susceptibility to long-term health outcomes related to their primary disease and treatment.To report on the number of cancer survivors and incident cancer cases in the period 1960-2009 in Israel, in order to provide data on the scope of the challenge Israel's health care funds face.The Israel National Cancer Registry (INCR) database was used to identify new cancer cases diagnosed during the period 1960-2009. Lifetable analysis was used to assess changes in cumulative survival and population prevalence of cancer survivors throughout the 50 year study period.Almost 600,000 invasive cancer cases were diagnosed during the period 1960-2009 (overall absolute survival rate 54%). Within this time period, the number of new patients diagnosed with cancer increased fivefold and that of cancer survivors ninefold. The absolute survival of cancer patients and the prevalence of cancer survivors in the general population significantly increased with time from 34% and 0.5%, respectively (1960-1969), to 62% and 1.9%, respectively (2000-2009). Cumulative absolute survival for 5, 10 and 15 years following diagnosis increased with time as well.The INCR database is useful to assess progress in the war against cancer. The growing numbers of cancer survivors in Israel present a challenge to the national health and social services system.

Background. There are concerns about growing barriers to cancer research. We explored the characteristics of and barriers to global clinical cancer research. Methods. The American Society of Clinical Oncology International Affairs Committee invited 300 selected oncologists with research experience from 25 countries to complete a Web-based survey. Fisher's exact test was used to compare answers between participants from high-income countries (HICs) and low- and middle-income countries (LMICs). Barriers to clinical cancer research were ranked from 1 (most important) to 8 (least important). Mann-Whitney's nonparametric test was used to compare the ranks describing the importance of investigated obstacles. Results. Eighty oncologists responded, 41 from HICs and 39 from LMICs. Most responders were medical oncologists (62%) at academic hospitals (90%). Researchers from HICs were more involved with academic and industry-driven research than were researchers from LMICs. Significantly higher proportions of those who considered their ability to conduct academic research and industry-driven research over the past 5 years more difficult were from HICs (73% vs. 27% and 70% vs. 30%, respectively). Concerning academic clinical cancer research, a lack of funding was ranked the most important (score: 3.16) barrier, without significant differences observed between HICs and LMICs. Lack of time or competing priorities and procedures from competent authorities were the second most important barriers to conducting academic clinical research in HICs and LMICs, respectively. Conclusion. Lack of funding, lack of time and competing priorities, and procedures from competent authorities might be the main global barriers to academic clinical cancer research.

The drugs cisplatin and gentamicin are given consecutively to various cancer patients suffering from infections. Little information exists about the ultrastructural alterations of kidney glomeruli caused by treatment with these drugs. Renal glomeruli of guinea pigs treated with cisplatin alone and in combination with gentamicin were studied by transmission electron microscopy. The findings revealed foci of damage induced by cisplatin and especially by cisplatin/gentamicin in all glomerular components: glomerular capillaries, including their endothelial cells; basement membrane, epithelial podocytes, mesangial cells, and parietal cells of Bowman's capsule. The damage was expressed by endothelial cytoplasmic extrusions into the vascular lumen, thickening and lamination of capillary basement membrane, focal foot process fusion of podocytes, vacuolization in cytoplasm of endothelial cells of epithelial podocytes and of parietal cells, and the presence of lipid bodies and myeloid bodies in all glomerular cell types. Additionally, injurious effects to cytoplasmic organelles such as mitochondria, nuclei, and endoplasmic reticulum were observed. The results indicate that cisplatin alone and in combination with gentamicin is toxic to renal glomerular tissue. Since these drugs were previously found toxic for strial capillaries in the inner ear and since the main glomerular component is the glomerular capillaries, potential vascular damage and vascular complications in different body systems have to be taken into consideration when these drugs are needed in clinical use.

BACKGROUND In the current study, the authors attempted to surmount the deficiencies of previous surveys and elicit information regarding the use of alternative treatments of cancer worldwide. METHODS The International Union Against Cancer (UICC), an international, nongovernment volunteer organization, E-mailed a questionnaire concerning alternative therapy use to its members. RESULTS A total of 83 responses from 33 countries were received. Descriptive analyses of this dataset were conducted, indicating the existence of a large and heterogeneous group of unproved remedies used to treat cancer in both developed and developing countries around the world. CONCLUSIONS Improved public education concerning the importance of early medical attention and the value of documented cancer therapies, the wider availability of useful cancer treatments, and public policies that are sensitive to the patient's need to play a meaningful role in his or her own care are required. Cancer 2001;91:1390–3. © 2001 American Cancer Society.

Bilateral breast cancer is traditionally considered an indirect indicator of inherited predisposition to cancer. To appreciate the contribution of genetic determinants to bilateral breast cancer in Jewish women we genotyped 55 such women for the three predominant mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) that account for the overwhelming majority of BRCA mutations in high-risk Jewish families. Among women with bilateral breast cancer, 17 mutation carriers (17/55; 29.6%) were identified. Individual mutation frequencies were 18.5% (10/55) for 185delAG, 3.7% (2/55) for 5382insC and 7.4% (5/55) for 6174delT. Carrier rate was significantly higher (P < 0.0016) in women with bilateral breast cancer whose first tumour was diagnosed at or before 42 years of age (82%; 14/17) than in women diagnosed after 42 years of age (7.9%; 3/38). Among patients with bilateral breast cancer and positive family history 45% (14/31) carried a BRCA mutation. Of these 86% (12/14) had one breast cancer diagnosed at or before 42 years of age. Our results suggest that bilateral breast cancer per se, in most cases, does not reflect genetic predisposition, unless associated with early age of onset (first tumour diagnosed at or before 42 years of age). Although the relationship between young age and carrier state in women with bilateral breast cancer is strong, no significant association between family history and carrier state was found. We can thus speculate that women with early onset breast cancer who carry a BRCA1 or BRCA2 mutation are prone to acquire a second breast tumour.

BACKGROUND Radiation therapy (RT) to the pelvis has been associated with an increased risk of bladder carcinoma, as well as other malignancies. However, no controlled studies have previously explored the risk of second malignancies after RT for prostate carcinoma. METHODS A retrospective cohort study was conducted utilizing data from the Surveillance, Epidemiology, and End Results Program (SEER) of the U. S. National Cancer Institute from 1973-1990. The standardized incidence ratio (SIR), adjusted for age, was calculated as an estimate of the relative risk (RR) of developing a second malignancy after prostate carcinoma for radiated and nonradiated prostate carcinoma patients separately. RESULTS The cohort was comprised of 34,889 prostate carcinoma patients who had undergone RT, and 106,872 who had not. After 8 years, the risk of bladder carcinoma was elevated for the RT group (RR 1.5; 95% confidence interval [CI], 1.1-2.0) but not for the non-RT group (RR 1.0; 95% CI, 0.7-1.2). There was an elevated risk of bladder carcinoma for the RT group at 5-8 years as well (RR 1.3; 95% CI, 1.0-1.7). No elevations in risk were observed for rectal carcinoma, acute nonlymphocytic leukemia, or chronic lymphocytic leukemia for either RT patients or non-RT patients. CONCLUSIONS The risk of bladder carcinoma is elevated several years after RT for prostate carcinoma, but this elevation is not dramatic. There is no increased risk of rectal carcinoma or leukemia after this type of radiation exposure. Cancer 1997; 79:1600-4. © 1997 American Cancer Society.

BACKGROUND. We designed a protocol with the goal of improving the disease free and overall survival of patients with previously untreated Stage IV nasopharyngeal carcinoma (NPC). The regimen consisted of intensive induction chemotherapy followed shortly thereafter by radiation therapy. METHODS. Between March 1986 and March 1992, 27 patients with T3-4, N2-3, M0 squamous cell carcinoma of the nasopharynx were treated with 2 cycles of chemotherapy, using cisplatin, 100 mg/m 2 intravenously, on Day 1, and 5-fluorouracil (5-FU), 1000 mg/m 2 per day continuous infusion, on Days 2-5. The second cycle was given on Day 16 and was followed by radiotherapy (RT), 70 Gray, given on Day 31. RESULTS. The objective response rate to chemotherapy was 93%, with a 37% complete response (CR) rate and a 56% partial response (PR) rate. The overall CR rate after RT was 85%. With a median follow-up of 60 months, the overall actuarial survival rate was 66%. Patients who had a CR after chemotherapy had a superior survival probability (100%). Toxicity was tolerable, without lethal complications. CONCLUSIONS. This study demonstrates that cisplatin/5-FU chemotherapy given in an intensive schedule and followed shortly thereafter by radical RT can improve the CR rate and survival of patients with locally advanced NPC, with tolerable toxicity.

Data from 29,845 patients with lymphomas, 981 of whom had lymphoma as a second primary tumor, registered in the Surveillance Epidemiology and End Results (SEER) program in the U.S.A. between 1973 and 1986 were analyzed. The characteristics of the 274 patients with lymphoma as a second tumor who had received chemotherapy and/or radiotherapy for their primary tumor (SEP PT) were compared with 675 patients with second primary lymphomas who had no prior treatment (SEP NT) and with patients with single lymphomas (SIP). Patients with SEP PT disease had a significantly higher percentage of intermediate and high-grade tumors (80%) compared to those with SEP NT or SIP tumors (73% and 72%, respectively). The survival of all patients with SIP tumors did not differ from those with SEP tumors, but the median survival of those with SEP PT disease was shorter than for SEP NT disease. This was most probably due to the high percentage of intermediate and high-grade lymphomas in the SEP PT group. This was statistically significant in the group treated by combined chemotherapy and radiotherapy but not in those treated by a single modality alone. These findings relating to a worse prognosis in patients with SEP PT lymphoma are in line with our previous observations of a poor survival in patients with other multiple primary tumors.

A cancer-registry-based study was conducted to investigate the survival patterns associated with metachronous colorectal tumors and to compare the survival of patients with single and metachronous colorectal tumors. The study included all 1,396 White patients with metachronous colorectal tumors diagnosed among 143,283 patients with primary colorectal tumors reported between 1973-1986 to the SEER program. The influence on survival of age at diagnosis, site of tumor and stage was evaluated by means of multivariate survival analysis, using Cox Proportional Hazards Models. Metachronous tumors developed more often following left-colon tumors. Stage distribution of the second tumors was better than that of single 47% of the second tumors were discovered in regionally-advanced or distant-metastatic stages. Survival from the second tumor diagnosed in the rectum was worse than that of a single tumor in the same stage and site. Only the stage of the second tumor was found to influence survival from metachronous tumors. The relatively high rate of diagnosis of advanced second colorectal tumors may reflect either improper follow-up after the diagnosis of the first tumor, or more aggressive biological characteristics of the second tumors.

Background. Most current lymphoma protocols limit vincristine dose to 2 mg per single dose. Because a lower dose of vincristine may be associated with poorer outcome, there is some rationale to increase the dose of vincristine. Methods. The feasibility of full dose vincristine (i.e., 1.4 mg/m2 without 2-mg dose limit) was prospectively evaluated in lymphoma patients treated with various combinations. After an initial dose of 1.4 mg/m2, patients were carefully monitored, and dose was modified according to toxicity. Results. One hundred and four consecutive patients (31 with Hodgkin's disease and 73 with non-Hodgkin's lymphoma), aged 18–78 years were evaluated. The first dose was greater than 2 mg in 90% of the patients. The mean actual dose (percent of projected dose) was 100% in the first course and gradually decreased to 64% in the eighth course. The mean actual dose intensity of vincristine (percent of projected dose intensity) during the initial six cycles of prednisone, methotrexate, calcium leucovorin, doxorubicin, cyclophosphamide, etoposide, and mechlorethamine, vincristine, procarbazine, prednisone (ProMACE/MOPP), cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), and MOPP/doxorubicin, bleomycin, and vinblastine (MOPP/ABV) was 82% and MOPP/doxorubicin, bleomycin, and vinblastine was 82%, 83%, and 87%, respectively. Symptoms of neuropathy developed in 92% of the patients and were usually of mild or moderate severity. Toxicity included World Health Organization (WHO) Grades 3 and 4 constipation in 10 (10%), and WHO Grade 3 peripheral neurotoxicity in 16 (15%) patients. Rapid improvement was usually noticed within a few weeks after withdrawal of vincristine. The median duration of symptoms from discontinuation of vincristine was 3 months for paresthesiae and motor weakness and 5 months for muscle cramps. Conclusions. Full dose vincristine in lymphoma protocols is feasible but is associated with increased toxicity. The therapeutic advantage of full dose vincristine has yet to be proven.

Background. Ionizing radiation is a lung carcinogen in a variety of settings, including after breast cancer radiation therapy. The authors explored whether cigarette smoking and breast cancer radiation therapy have a multiplicative effect on the risk of subsequent lung cancer. Methods. This case-control study investigated women registered with primary breast cancer in the Connecticut Tumor Registry who developed a second malignancy between 1986 and 1989. Those diagnosed with a subsequent primary lung cancer were compared with those diagnosed with a subsequent nonsmoking, nonradiation-related second malignancy, and age-adjusted odds ratios were calculated with logistic regression. Results. No radiation effects were observed within 10 years of initial primary breast cancer. Among both smokers and nonsmokers diagnosed with second primary cancers more than 10 years after an initial primary breast cancer, radiation therapy was associated with a 3-fold increased risk of lung cancer. A multiplicative effect was observed, with women exposed to both cigarette smoking and breast cancer radiation therapy having a relative risk of 32.7 (95% confidence interval [CI], 6.9–154). The radiation carcinogenic effect was observed only for the ipsilateral lung and not for the contralateral lung both in smokers and nonsmokers. Conclusions. Breast cancer radiation therapy, as delivered before 1980, increased the risk of lung cancer after ten years in nonsmokers, and a multiplicative effect was observed in smokers. For both smokers and non-smokers, this effect was observed only for the ipsilateral lung and not the contralateral lung. Modern techniques, however, significantly decrease the radiation dose to the lungs, which may decrease the risk of lung cancer. Nonetheless, due to the available choices in early-stage breast cancer treatment, current practices may need to be revised for young breast cancer patients who smoke. Cancer 1994: 73:1615–20.

The results of two schedules of the combination of etoposide, doxorubicin, and cisplatin (EAP) in gastric cancer are reported. EAP-1 was administered as originally reported and consisted of i.v. doxorubicin (adriamycin) 20 mg/m2 on days 1 and 7, i.v. cisplatin 40 mg/m2 on days 2 and 8 and i.v. etoposide (VP-16) 120 mg/m2 (100 mg/m2 in patients aged 60-65) on days 4-6. EAP-2 consisted of i.v. adriamycin 40 mg/m2 on day 1, i.v. cisplatin 80 mg/m2 (total dose per cycle) given in 3 divided doses on days 1-3 and i.v. VP-16 100 mg/m2 on days 1-3. Cycles of the two regimens were repeated on day 22. Drug doses were reduced in patients over 65 years of age. Twenty patients were treated with EAP-1 and 43 with EAP-2. Forty-five of the 63 patients included in this study had advanced gastric carcinoma, 16 had radically resected stage III disease, and 2 had metastatic signet ring cell carcinoma of unknown primary origin. Thirty-eight patients with advanced gastric adenocarcinoma were evaluable for response. The response rate for EAP-1 (6/13, 46%) was similar to that of EAP-2 (13/25, 52%). The median duration of response was 8 months for EAP-1 and 6.5 months for EAP-2. Myelotoxicity of EAP-1 was much more severe than that of EAP-2. Hospitalization due to granulocytopenic fever was required in 15/78 (19%) EAP-1 versus 20/215 (9%) EAP-2 courses. Toxic deaths occurred in 3/20 treated with EAP-1 and in 1/45 treated with EAP-2. The difference in toxicity between the two regimens could not be attributed to differences in patients' characteristics or to dose intensity. We conclude that the modified EAP regimen (EAP-2) is effective in the treatment of gastric cancer and is less toxic than the original EAP.

Marking the annual "Door Knock" Fundraising Campaign Jubilee, this article provides an overview of the Israel Cancer Association (ICA) activity for patients and against the disease, that comply with the principles of the World Cancer Declaration (WCD) of the UICC (Union for International Cancer Control). To elucidate, as a voluntary organization, all of ICA's resources are derived exclusively from public contributions--with no funding from the government budget. This independence enables ICA to operate according to strictly professional criteria, while maintaining a global and national point of view and vision. ICA activity will be presented with respect to the international treaty, from monitoring the disease at the national level, to activity to promote research, prevention methods, early detection, enhancing treatment modalities and rehabilitation, and maintaining quality of life for patients and survivors. This presentation will also provide an overview of how ICA's initiative, in close collaboration with the Ministry of Health, and the HMO's, white relying on the volunteer activity of members of the ICA professional committees, and that of many other volunteers, leads Israel to significant accomplishments in each one of the treaty sections. These activities have resulted in concrete achievements at the national level, positioning Israel high on the global scale.

Background. Radiation, including radiation therapy (RT) for a variety of conditions, is known to be a lung carcinogen. Methods. Data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute for 1973-1986 were utilized to investigate whether RT for breast cancer affects the risk of subsequent lung cancer. The relative risk was calculated by comparing the incidence rate in patients with irradiated breast cancer with that in those with nonirradiated breast cancer. Results. It was found that the risk of lung cancer overall was increased in women who underwent irradiation compared with those who were not irradiated 10 years after the initial breast cancer diagnosis with a relative risk of 2.0 (95% confidence interval, 1.0-4.3). In addition, the risk of lung cancer was in the ipsilateral lung compared with the contralateral lung for irradiated women. This increase was observed after 10 years for lung cancer overall and for the three major histologic subgroups (small cell, squamous cell, and adenocarcinoma). Specific information on RT doses and treatment plans and cigarette smoking were not available. Conclusions. It was concluded that RT for breast cancer may increase the risk of lung cancer after a latency period of 10 years.

Background. A second primary tumor (SPT) in the breast is the most common one seen in clinical practice. There are conflicting reports regarding the incidence and survival of patients with SPT in the breast. Methods. To elucidate this, data on 139,932 patients with primary breast cancer, reported to the Surveillance, Epidemiology, and End Results Program between 1973 and 1986, were analyzed. Of these, 3431 patients had a contralateral metachronous breast cancer (interval, > 6 months). Results. Survival from the date of diagnosis of the metachronous breast tumors was compared with that of patients with single breast tumors, controlling for age at diagnosis, stage, race, and treatment. In the multivariate analysis, age and stage at diagnosis of first and second tumors were the only variables that significantly influenced survival. The survival of patients with localized SPT was similar to that of patients with a localized single breast tumor. Patients with regionally advanced SPT lived for a shorter time than did corresponding patients with only one tumor. Conclusions. Patients with single breast cancer were at increased risk of having a SPT in the breast. As a result, efforts for early detection by physical examination and mammography of survivors of single breast cancer are advocated because the survival of patients with a localized SPT in the breast is as good as that of those with a single localized tumor. Cancer 1993; 71:172-6.

The clinical characteristics of 240 patients with sarcoma as a second metachronous primary neoplasm (SPN) were compared with those of 8,815 patients with sarcoma as a single tumor. The data were obtained from patients registered during the period 1973-1986 in the Surveillance, Epidemiology and End Results (SEER) Program in the United States. Seventy-four of the 240 SPN patients had postirradiation sarcoma (PIS) while the other 153 patients developed the sarcoma as a second tumor in an area which was not exposed to prior radiotherapy (non-PIS). The stage of disease at diagnosis was more advanced in patients with PIS than in those with single sarcomas but the difference did not reach statistical significance. Overall, in comparable clinical stage localized and regional disease there was no statistically significant difference in survival between PIS and non-PIS sarcoma patients after adjusting for age. The survival of patients with localized or regionally advanced sarcoma as a second tumor was significantly worse than of those with single sarcomas with the same stage. There was no difference in survival between first or second sarcomas with metastatic disease.

This is a retrospective analysis of 147 evaluable patients, with histologically proven renal cell carcinoma, who were referred to our center between 1977 through 1988. All patients with disease limited to the kidney underwent nephrectomy. Post-operative megavoltage irradiation, with a median dose of 46 Gy, was given to 56 patients, using parallel opposing portals, or multiple field technique. Five and 10 year actuarial survivals in irradiated patients (Rt+) were 50 and 44%, respectively, and in non-irradiated patients (Rt-) 40 and 32%, respectively. The disease recurred locally in a total of 19 patients; 16 had tumor bed recurrence and three had scar recurrence. Local recurrence by stage was as follows: T 2 N 0 M 0 : RT + 017, RT- 228; T 3 N 0 M 0 : RT+ 437 (10%), RT - 1130 (37%) ( p 4 N 0 M 0 : RT + 12, RT - 15. Two of the local recurrences in irradiated patients developed in a surgical scar which was not included in the treatment volume. Significant toxicity developed in three patients (5%)). It is concluded that post-operative irradiation can reduce local recurrence rate in T 3 N 0 M 0 renal cell carcinoma. It is recommended that the surgical scar should always be included in the treatment volume and irradiated to a full dose.

The negative predictive value (PV-) and positive predictive value (PV+) of gallium-67 scintigraphy and computed tomography (CT) were compared after treatment in 43 patients with Hodgkin disease and in 56 patients with non-Hodgkin lymphoma. The usefulness of these studies in predicting survival was also evaluated. In patients with Hodgkin disease, the PV- of Ga-67 scintigraphy was 0.84 and of CT was 0.88. The PV+ was 0.80 for Ga-67 studies and only 0.29 for CT. In patients with non-Hodgkin lymphoma, the PV- of Ga-67 scintigraphy was 0.84 and of CT was 0.80. The PV+ was 0.73 and 0.35, respectively. For both groups, the differences in disease-free survival between patients with negative and positive Ga-67 studies were significant (P less than .05 in Hodgkin disease and P less than .001 in non-Hodgkin lymphoma), but the differences were not significant for CT. These data show that, after treatment of patients with lymphoma, Ga-67 scintigraphy is a good predictor of clinical outcome and can be used beneficially in patient treatment.

There is a known increased risk for the co-occurrence of both breast cancer and colorectal cancer in the same women, presumably as a result of either shared reproductive hormonal or environmental risk factors. Using data from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute, the authors investigated whether there is a similar relationship between breast cancer, colorectal cancer, and prostate cancer in men. The observed-expected ratio was not significantly elevated for either colorectal cancer after breast cancer or for breast cancer after colorectal cancer in men. There was an increased incidence of prostate cancer after colorectal cancer, but this relationship was not present in the opposite direction and is believed to result from detection bias. There was an increased incidence of breast and colorectal cancer in women. These results suggest that the observed breast and colorectal cancer relationship in women may be a result of shared reproductive hormonal factors.

All European countries are facing common challenges for delivering appropriate, evidence-based care to patients with cancer. Despite tangible improvements in diagnosis and treatment, marked differences in cancer survival exist throughout Europe. The reliable translation of new research evidence into consistent patient-oriented strategies is a key endeavour to overcome inequalities in healthcare. Clinical-practice guidelines are important tools for improving quality of care by informing professionals and patients about the most appropriate clinical practice. Guideline programmes in different countries use similar strategies to achieve similar goals. This results in unnecessary duplication of effort and inefficient use of resources. While different initiatives at the international level have attempted to improve the quality of guidelines, less investment has been made to overcome existing fragmentation and duplication of effort in cancer guideline development and research. To provide added value to existing initiatives and foster equitable access to evidence-based cancer care in Europe, CoCanCPG will establish cooperation between cancer guideline programmes. CoCanCPG is an ERA-Net coordinated by the French National Cancer Institute with 17 partners from 11 countries. The CoCanCPG partners will achieve their goal through an ambitious, step-wise approach with a long-term perspective, involving: 1. implementing a common framework for sharing knowledge and skills; 2. developing shared activities for guideline development; 3. assembling a critical mass for pertinent research into guideline methods; 4. implementing an appropriate framework for cooperation. Successful development of joint activities involves learning how to adopt common quality standards and how to share responsibilities, while taking into account the cultural and organisational diversity of the participating organisations. Languages barriers and different organisational settings add a level of complexity to setting up transnational collaboration. Through its activities, CoCanCPG will make an important contribution towards better access to evidence-based cancer practices and thus contribute to reducing inequalities and improving care for patients with cancer across Europe.

Second primary neoplasms are occurring with increasing frequency. Despite growing literature on the incidence and etiology of this phenomenon, very little has been documented about the clinical aspects and biological behavior of these tumors. As our experience has hinted at a worse prognosis for second primaries, we thought it of interest to study this phenomenon for one type of tumor. We reviewed 32 cases of thyroid cancer arising as a second neoplasm in patients with Hodgkin's disease and compared various clinical characteristics to reported series of de novo (non-radiation-induced) thyroid cancer. Thyroid cancer, as a second primary, occurred more frequently in males with a more malignant histology and was diagnosed at a more advanced stage. The survival appears to be worse. The behavior of radiation-induced thyroid cancer in a host with prior malignant neoplasia appears to be more aggressive than that of both de novo (non-radiation-induced) thyroid cancer and radiation-induced thyroid cancer in a host with no prior malignancy. The selected nature of the cases precludes any firm conclusions. This type of information should be collected prospectively for all secondary malignancies as it may have an impact on the clinical management of these patients.

The damaging effects on the liver tissue of treatment with cisplatin followed by the aminoglycoside antibiotic gentamicin were studied in guinea pigs. The ultrastructural findings revealed foci of damage in the liver parenchyma, including its vascular component. Injurious effects to cytoplasmatic organelles such as mitochondria and endoplasmic reticulum as well as to nuclei were observed. In addition, abundance of lysosomes, autophagic vacuoles, and amorphous-granular bile in the lumina of bile canaliculi was found. Focal sinusoidal lining damage and capillarization of sinusoids were also present. In vascular lumina, some erythrocytes showed a deformed shape ("ropalocytosis"). Taken together, these findings indicate that the combined treatment with cisplatin followed by gentamicin is toxic to components of liver tissue. Since toxic changes have been shown in vessels of the inner ear and in renal-glomerular capillaries, the present observations of hepatotoxicity indicate the potential vascular damage to various tissues. The injurious effects of the cisplatin-aminoglycoside combination should be considered during its use in clinical conditions.

The use of complementary and alternative medicine has increased over the last decade in the western world.To evaluate the extent and characteristics of CAM use among cancer patients in northern Israel.Telephone interviews were conducted with 2,176 newly registered cancer patients or their family members, at least 1 year following referral.The rates of CAM use varied significantly according to demographic characteristics and chemotherapy treatment, from 3% in the basically educated elderly group up to 69% of educated Israeli-born Jews younger than 70 years receiving chemotherapy. The overall rate of CAM use was 17%. The most influential factors determining CAM use were academic or high school education, chemotherapy treatment, Israel as country of birth, and age 41-50 years. All patients used CAM in addition to conventional therapies. Less than half of them reported it to their physicians. The most frequently used treatments were various chemical, biological, botanic and homeopathy remedies. Friends and relatives were the main recommenders of CAM. Most CAM users reported that they used CAM because they believed it "strengthens the immune system," alleviates side effects of chemotherapy, improves quality of life, and helps to overcome pain and stress; 62% of them reported subjective beneficial effects.A predicting module of CAM user patients was built that may help physicians initiate conversations with their patients on CAM use. Expanding physicians' knowledge on CAM methods will encourage them to provide additional advice, promote the use of beneficial therapies, and inform patients about potentially harmful methods.

This protocol was designed to achieve an improvement in the overall and disease-free survival in locally advanced, previously untreated carcinoma of the head and neck. 53 patients (pts) with locally advanced Stages III and IV, MO squamous cell carcinoma of the nasopharynx, larynx, paranasal sinuses, oral cavity, oropharynx, hypopharynx and one of unknown origin were treated with intensive chemotherapy followed shortly thereafter by radiotherapy. Induction chemotherapy consisted of two cycles of cisplatin 100 mg/m2 over 60 min on day 1, plus 5FU 1000 mg/m2 continuous infusion over 24 h on days 2-5, with a 10-day interval between the two cycles, followed by definitive radiotherapy after 10 days. The overall response rate to chemotherapy was 79%, with a 28% complete response (CR) rate and a 51% partial response (PR) rate. The overall CR rate after radiotherapy was 70%. With a median follow-up period of 48 months, the 5-year actuarial survival and disease-free survival rates were 67% and 45%, respectively. No difference was found in the survival probability of pts with carcinoma of the nasopharynx, larynx or other primary sites. The survival of pts with a performance status (PS)or = 1 was better than pts with PS1, 72% versus 51% (not significant). The survival probability of complete responders to chemotherapy was superior than the survival of non-complete responders to chemotherapy, 100% versus 54% [P = 0.001]. The main toxicity was mucositis during radiotherapy. In conclusion, this treatment regimen demonstrated a high CR rate and survival probability in pts with locally advanced and mostly inoperable head and neck cancer.

Background The study of second primary malignancies may give clues to the etiology of various cancers. Little is known about risk factors for pancreatic carcinoma; therefore, its occurrence as a second primary malignancy was investigated. Methods Data from the Surveillance, Epidemiology, and End-Results (SEER) program were used for the period from January 1, 1973 through December 31, 1990. Person-years of follow-up for various cancer sites were calculated, excluding the initial 6 months after diagnosis, and were multiplied times the age- and sex-specific incidence rates for pancreas cancer to calculate the expected number of second primary pancreas cancer cases. The observed number of cases was divided by the expected number to estimate the relative risk (RR) of pancreas cancer as a second primary cancer, and 95% confidence limits were calculated. Results The risk of second primary cancer was elevated after lung cancer for men (RR 1.3, 95% CI 1.0-1.6) and women (RR 2.5, 95% CI 1.9-3.2). An elevation in risk also was found after head and neck cancer in women (RR 1.8, 95% CI 1.2-2.5) and bladder cancer in women (RR 1.5, 95% CI 1.1-2.0), but not in men. Other significant elevations were found after prostate cancer (RR 1.2, 95% CI 1.1-1.3), and a decreased risk was found after lymphoma in men (RR 0.2, 95% CI 0.0-0.8). Conclusions Second primary pancreas cancer is increased after tobacco-related malignancies, particularly in females, supporting the role of cigarette smoking as a risk factor for pancreas cancer and suggesting a stronger effect of cigarette smoking for women. The elevation in risk after prostate cancer and the decreased risk after lymphoma in males need to be confirmed in other data sets.

Natural killer (NK) cell activity, the autologous mixed lymphocyte reaction (AMLR) and proportions of T cell subpopulations (CD3+/CD4+ and CD3+/CD8+) and NK cells (CD16+) were studied in 21 patients with bilateral primary breast cancer (BBC), 10 patients with single-breast cancer (SBC) and 20 healthy controls. All patients studied had no evidence of disease and had been off radiotherapy and/or chemotherapy for at least 1 year. Ten patients with BBC were also treated with tamoxifen. Patients with SBC had NK cell activity, AMLR responses and T cell subpopulations that were comparable to those of normal controls. In patients with BBC, a significant (P0.01) increase in NK activity compared to that in normal controls (42 +/- 13% versus 21 +/- 10%, effector-to-target cell ratio, 25:1) and a significant (P0.05) decrease in CD4+ T cell proportions (30 +/- 15% versus 49 +/- 13%) and absolute numbers (472 +/- 82/mm3 versus 953 +/- 131/mm3) were found. However, the proliferative response of BBC patients' T lymphocytes in AMLR was in the range of the normal controls. Lymphocytes derived from 10 BBC patients treated with tamoxifen exhibited NK cell activity that was comparable to that of normal controls and patients with SBC, and was significantly (P0.01) reduced compared to the pretreatment period. BBC patients who received tamoxifen also show a reduction in the proportion of CD4+ T cells and in AMLR proliferative responses, which decreased compared to levels in normal controls. Taken together, these results indicate that long-term tamoxifen treatment modulates immune responses in BBC patients.

One hundred and sixty-seven patients with metachronous bilateral breast cancer were diagnosed at the Northern Israel Oncology Center during the years 1950-1989. The group at high risk to develop a second breast tumor included Jewish women born in Europe whose first tumor was diagnosed when the patient was under the age of 55. The mean time interval between tumors was 88 months. Seventy percent of the patients were diagnosed within nine years of the diagnosis of the first tumor. The characteristics of the 27% of patients with single breast cancers who did not comply with follow-up recommendations were compared to those who did comply. Patients who were under follow-up had smaller tumor and less lymph node involvement. Nevertheless, their survival rate did not differ from those who did not keep their follow-up appointments. This was ascribed to the fact that follow-up procedures for many years used mainly clinical examination and this was not enough to decrease mortality. The diagnosis of non-palpable breast cancer by routine yearly mammography has proved to reduce mortality in patients over the age of 50 with single breast cancers. Therefore, yearly mammography of the contralateral breast in patients with single breast tumors must be done in order to increase the cure rate of contralateral breast cancer. Less patient delay in diagnosis was found before the diagnosis of the second tumor than in patients with a single tumor.

The clinical characteristics of 152 patients diagnosed with two primary metachronous tumors--one or both of them in the colon--were studied. Nineteen patients had both primary tumors in the colon (Group I), 59 had the first primary tumor in the colon and the second tumor elsewhere (Group II), and 74 had the second primary tumor in the colon and the first primary tumor elsewhere (Group III). The group in which the second primary tumor was in the colon included significantly more female patients than did the other two groups, with a younger median age at diagnosis of first tumor. The median time interval between the two primary tumors was 44, 57, and 62 months in Groups I, II, and III, respectively. The number of clinic visits during the year before diagnosis of the second primary was similar in all groups, but only 60 percent of the patients kept their follow-up appointment. In most instances, the diagnosis was made after the patients' symptoms, although only a small percentage of the second primary tumors (15-30 percent) were diagnosed during routine follow-up. The second primary tumor occurred in the field of radiotherapy of the first primary tumor in 27 of 35 patients who received radiotherapy. To increase the number of patients diagnosed in an earlier stage of disease, they should be urged to keep their follow-up appointment, and physicians following patients with single tumors should be aware of the increased likelihood of a second tumor. To increase the cure rate of those tumors, efforts toward early diagnosis are warranted. This includes physical examination and mammography to detect breast cancer in women, annual occult blood tests and rectal examination, and sigmoidoscopy or colonoscopy at three-year intervals to detect colon cancer early.

The clinical characteristics of 183 patients with second primary neoplasms in the head and neck region were compared with those of 20,598 patients with one primary tumor in the same region registered during the period 1973 to 1984 in the Surveillance, Epidemiology and End-Results Program. Second primary head and neck tumors were more likely to be diagnosed in a localized stage (47%) than if diagnosed as a single primary tumor (43%), but this difference was not significant. The tumor grade distribution was comparable in both groups. Using Cox proportional hazards modeling with age, sex, race, and stage as covariates, the median survival of patients with first and second head and neck cancer was identical (50 months). The survival of patients with localized second head and neck cancer was shorter than that of patients with single localized tumors (55 versus 102 months, P less than 0.026). Survival for regional tumors was similar (18 versus 21 months, not significant). The 84 second head and neck cancers in which the first head and neck cancer received radiation therapy (RT) had a median survival of 20 months; the 98 cases without prior RT had a median survival of 35 months. The high incidence of localized second cancers was probably due to the more intense surveillance. The worse survival in this group may be a result of prior RT or biologic characteristics of the tumor.

Concentrations of bleomycin labeled with cobalt 57 (Co-bleo) over time were measured in vivo in 17 patients with 32 sites of lymphoma and 18 patients with lung tumors after administration of the same dose of bleomycin. There were marked variations in individual tumor drug concentrations even among tumors with the same histologic type, indicating that the tumor concentration of this drug in individuals cannot be predicted from the administered dose. Also, tumor concentration could not be predicted from the area under the concentration over time curve (AUC) of Co-bleo in the blood; there was no correlation (r = 0.53) between the AUC and the concentration in the tumor at any point in time between 30 minutes and 8 hours after injection. There was no significant difference in the percent of the injected dose per milliliter (%ID/ml) which was delivered to the tumor when low and high amounts of bleomycin were administered to the same patient. Also, a good correlation (r = 0.88) between the %ID/ml over time was found when injection of low and high doses of bleomycin were compared. The results indicate that using quantitative single photon emission computed tomography (SPECT) and a labeled tracer dose it is possiblemore » to predict what fraction of the dose of a chemotherapeutic drug will concentrate in an individual patient's tumor in vivo. They also show that, for bleomycin, escalation of dose will result in a proportional increase of tumor concentration. This increase depends on individual properties of tumors which can be measured quantitatively in vivo by SPECT and are expressed as percent of %ID/ml of tumor tissue.« less

Medical records of seven patients treated within a 20 year period for malignant melanoma during pregnancy were reviewed. No significant detrimental prognostic effects could be attributed to pregnancy. The current literature on melanoma and pregnancy is discussed. Based on this, pregnancy seems not to be contraindicated in melanoma patients.

Ninety-five newly diagnosed patients with diffuse large cell lymphoma (DLCL) treated by cyclophosphamide (CTX), doxorubicin (ADM), vincristine (VCR), and prednisone (CHOP regimen) chemotherapy were evaluated for survival factors including dose intensity (DI). DI calculations were done for the initial cycles needed to achieve maximal response. The medians of the relative DI for CTX, ADM, and VCR were 0.9, 0.86, and 0.79, respectively. The median of the average relative DI (ARDI) was 0.83 (range, 0.28 to 1.14). The univariate analysis of potential prognostic variables showed that the following significantly decreased the survival rate: age older than 60 years (P = 0.0005), Stage III to IV (P = 0.02), male sex (P = 0.03), and all four DI variables (CTX, ADM, VCR, and ARDI) less than the median (P = 0.01 to 0.0001). A multivariate analysis by the stepwise proportional hazards model of Cox indicated that the factors predicting a poor prognosis were ARDI less than the median (P = 0.0003) and age older than 60 years (P = 0.02). A multivariate survival analysis of those who achieved complete remission showed ARDI less than the median (P = 0.0003), CTX less than the median (P = 0.02), and Stage III to IV (P = 0.02) to be the most negative factors regarding survival. In conclusion, a high DI in the initial cycles of CHOP chemotherapy for DLCL has a significant positive impact on survival.

The results of planar and single photon emission computed tomography (SPECT) gallium-67 scintigraphy performed before and after treatment were compared in 77 patients with lymphoma at 240 sites. Before treatment, the sensitivity of planar scintigraphy was 78% and the specificity was 97%; after treatment, 84% and 96%, respectively. Before treatment, SPECT had a sensitivity of 85% and a specificity of 98%; after treatment, 92% and 99%, respectively. In addition, SPECT allowed better anatomical localization and showed the entire extent of lesions at 36 sites. SPECT was of special value after treatment in excluding disease at 16 sites with residual masses seen at computed tomography (CT). Long-term follow-up in these patients showed that their condition was in complete remission and that the CT appearance of a residual mass does not always mean residual cancer. Thus, Ga-67 SPECT is a suitable imaging technique for monitoring the response of lymphoma to treatment.

A total of 30 consecutive patients with refractory or relapsing non-Hodgkin's lymphoma (NHL) were treated with a combination of dexamethasone, etoposide (VP-16), ifosfamide, and cisplatin (DVIP). In all, 9 subjects (30%) showed a partial response and 10 (33%) achieved a complete response (CR) lasting from 2.5 to 24+ months. Aggressive histology, no prior therapy with VP-16, a CR to previous chemotherapy, and a treatment-free interval of greater than 6 months prior to the present study were associated with the high CR rate. DVIP caused pronounced myelosuppression (median granulocyte nadir and median platelet nadir, 380/mm3 and 73.000/mm3, respectively), but no drug-related death occurred. We conclude that DVIP is an effective salvage combination, especially in aggressive NHL, that produces acceptable toxicity.

BACKGROUND Cancer patients with single tumors live longer today due to earlier detection and improved treatment methods. For this reason, the authors see more patients who develop a second primary tumor. The etiology of the second tumor can be the same as the first, whether treatment-induced or unknown. The prognoses of these patients usually depend on the behavior of the second tumor. METHODS The authors investigated the lymphocyte subset in 88 of the more than 750 patients listed in the tumor registry at their treatment center who had at least one carcinoma of the breast or colon and a second primary of the same or another site. Mononuclear cells were obtained from heparinized blood by the standard fractionation Hypaque gradient centrifugation technique. Helper and suppressor cells were identified by using three murine monoclonal antibodies: CD3 for mature T lymphocytes, CD4 for helper inducer cells, and CD8 for suppressor cytotoxic cells. T-cell subset distribution was evaluated with flow cytometry. RESULTS Most values of CD3, CD4, and CD4/CD8 were lower in patients than in healthy controls. The values of CD4 and CD4/CD8 were lower in patients who had a second tumor in the colon rather than in the breast. CONCLUSIONS As tumors in patients with a second primary sometimes recur or the patient develops a third primary, the authors are prospectively following their patients to see whether those with immunosuppression have a greater tendency to develop recurrent disease or a third primary. Cancer 1999;85:2073–6. © 1999 American Cancer Society.

The combination of dexamethasone, etoposide (VP-16), ifosfamide and cisplatin (DVIP) was evaluated as a second line after adriamycin containing combinations in intermediate or high grade non-Hodgkin's lymphoma (NHL). 39 patients (pts) (median age 68 years) entered the study. Objective responses were seen in 29 pts (74%) and included complete response (CR) in 14 (36%). Median duration of CR was 12 months (mos) and that of partial response was 3.5 mos. 13/25 (52%) pts who responded with CR to adriamycin-based combinations responded with CR to DVIP (vs 1/14 who failed to respond with CR). Durable remissions (24 ± 57+ mos) continue in 4 pts who responded with CR to frontline therapy. Main toxicity was myelosuppression. Median WBC nadir was 1100/mm3 and median platelets nadir was 66,000/mm3. There was no treatment-related mortality. We conclude that DVIP is an effective second line in histologically aggressive NHL, associated with acceptable toxicity, and has a curative potential in pts with relapsing disease.

The toxic effects on the stria vascularis of treatment with cisplatin alone and combined with the aminoglycoside antibiotic, gentamicin, were studied in guinea pigs. The toxicity induced in albino and pigmented guinea pigs was investigated morphologically with light and transmission electron microscopy, and functionally by brainstem-evoked response audiometry. The results of hearing thresholds were variable, ranging from no change in one ear in some of the animals to a hearing loss of 20 dB in one or both ears when treated with low-dose cisplatin alone or in combination with gentamicin. Bilateral deafness resulted from high-dose cisplatin combined with gentamicin. The combined treatment produced prominent structural damage in the stria vascularis. The results should be considered when aminoglycoside therapy is required in conjunction with cisplatin.