Second Cancers In Patients Research Articles

Therapy-related acute promyelocytic leukemia: further insights into the molecular basis of the disease and showing the way forward in therapy

Acute myeloid leukemia (AML) occurring as a second cancer in patients, who were successfully treated for a prior neoplasm, has been reported with increased frequency partly due to the success of antineoplastic radiation and chemotherapy. Many of such therapy-related leukemias have been associated with recurring chromosomal abnormalities; this is suggestive of a specific interaction between certain chemotherapeutic agents and the genome with different drugs predisposing patients to specific translocations [1]. Although acute promyelocytic leukemia (APL) occurring after prior chemotherapy for other tumors has been infrequent, several recent reports have better characterized this entity and have suggested an increase in its incidence possibly due to an increased used of topoisomerase II inhibitors, particularly in the treatment of breast cancer [2,3]. In general, the clinical features, response to therapy and long-term outcome of patients with therapy-related APL appears not to be different from de novo cases of APL [2,3]. A recent report suggested that translocation breakpoints in APL occurring after exposure to topoisomerase II inhibitors such as mitoxanterone, etoposide and doxorubicin were clustered in ‘hot spots’ within PML and RARA and were common sites of mitoxantrone-induced cleavage by topoisomerase II [4]. The presence of preferential sites of DNA damage induced by mitoxantrone in PML and RARA genes was further corroborated by another study of 12 patients with multiple sclerosis (MS), who developed APL after therapy with mitoxantrone [5]. This was further suggestive of the specific interaction of the topoisomerase II poison with preferential sites on the genes involved which was independent of a predisposing genetic instability (as would be suspected in a patient with multiple cancers). In this issue of the journal, Aversa et al. report on a case of APL developing 4 years after receiving a combination of the Stanford V chemotherapy regimen with radiation in a patient with advanced Hodgkin lymphoma [6]. The topoisomerase inhibitors, doxorubicin and etoposide are amongst the agents used in the Stanford V regimen and as such, would be expected to predispose to the development of AML with associated translocation involving the specific cleavage sites. However, and perhaps somewhat surprisingly, according to the authors, this is the first reported case of APL in patients treated with the Stanford V regimen with the only other previous reported case of AML being associated with a translocation involving the chromosome band11q23. Of interest, Aversa et al. treated their patient successfully with the combination of all-trans retinoic acid (ATRA) and idarubicin and used a consolidation regimen including cytarabine, idarubicin, mitoxantrone and etoposide. This raises another question of what is the best regimen to treat a patient with secondary APL suspected to be the consequence of topoisomerase II inhibitor therapy? In addition to the intuitive concern for using the same agent to treat the disease as the one suspected to induce it, the issue of cumulative doses of anthracyclines and the attendant risk of cardiotoxicity has to be considered. The introduction of arsenic trioxide (ATO) as an effective treatment for relapsed APL and recent studies suggestive of a role for ATO in frontline therapy of patients have provided us with an alternative to anthracycline and ATRA based regimens used to treat patients with APL [7–9]. We have recently reported that the combination of ATRA, ATO, possibly with the addition of gemtuzumab ozogamicin but without chemotherapy is effective in producing molecular remissions that are durable [10]. In this issue of the journal, Ammatuna et al. report on the use of ATRA and ATO for consolidating the remission in a patient with secondary APL after mitoxantrone therapy for MS [11]. Their main incentive for using ATRA and ATO for consolidation was to avoid further cardiotoxicity in light of the patient's prior extensive mitoxantrone exposure. In light of our experience, as well as that of others, one can argue for the use of this combination for induction and consolidation in all patients who have a significant risk of anthracycline induced cardiotoxicity. There are other reasons that a ‘chemotherapy-free’ regimen may be particularly desirable. Patients with advanced age, poor organ function and poor performance status may not be good candidates for traditional cytotoxic chemotherapy and may benefit significantly from this approach. Furthermore, although the incidence of secondary myelodysplastic syndrome following treatment of APL with chemotherapy-based regimens is extremely low, there are several reported cases in the literature [12,13]. Therefore, if the ATRA plus ATO regimen is proven to be at least as effective as the standard chemotherapy plus ATRA regimens, it can be argued that it should be the preferred regimen in all patients, irrespective of their age, organ function or performance status. Ongoing clinical trials will attempt to address this question. In conclusion, despite significant strides in treating patients with APL, the story remains un-ended with future chapters hopefully introducing regimens with limited or no toxicity and universal success.

Usefulness of PET/CT for Detecting a Second Primary Cancer After Treatment for Squamous Cell Carcinoma of the Head and Neck

Patients with squamous cell carcinoma of the head and neck have been reported to have a high rate of second primary cancer of the upper aerodigestive tract. This study was performed to determine whether positron emission tomography/computed tomography (PET/CT) is useful for detecting a second primary cancer after treatment for squamous cell carcinoma of the head and neck. The PET/CT findings in 279 consecutive patients (211 men, 68 women; mean age 62 years) who had been treated for squamous cell carcinomas of the head and neck were examined and compared with the findings obtained by other imaging modalities, the biopsy results, and the clinical data. Thirty second primary cancers were documented in 28 of the 279 subjects. Based on PET/CT findings, the overall risk of a second primary cancer in 1 year was 9.9% and the risk in the upper aerodigestive tract region was 6.8% (19/279). PET/CT enabled early detection of a second cancer in patients treated for head and neck cancer.

High Rate of Second Malignancies after Reduced Intensity Double Cord Blood Transplants in Adults.

Reduced intensity conditioning (RIC) double cord blood transplantation is an effective strategy in adults to provide allogeneic donors for patients with uncommon HLA types. However, the risk of second cancers has not been established. We treated 53 patients with hematologic malignancies using a RIC regimen of fludarabine 30 mg/m2/day Days −8 through −3 (total dose 180 mg/m2), melphalan 100 mg/m2 Day −2 and rabbit antithymocyte globulin 1.5 mg/kg Days −7, -5, -3, -1 (total dose 6 mg/kg). Cord blood units were a 4/6 or higher HLA A, B, DR allele match with the patient and each other and achieved a minimum precryopreservation cell dose of 3.7 x 107 NC/kg. Twenty-one patients received GVHD prophylaxis with cyclosporine and mycophenolate mofetil and 32 patients received tacrolimus and sirolimus. Median age was 49 (range 19–67) years and the majority of patients had acute leukemia or relapsed lymphoma. Median follow-up was 27 months among the 29 patients still alive. Nine patients developed a second malignancy. Seven patients had lymphoma and two had MDS/MPD. The second cancers occurred at a median of 141 days (range 39 days-26 months) after transplant. Five second cancers (both MDS/MPD and 3 of 7 lymphomas) were donor derived; the origin of the others was not determined. Patients with Epstein Barr Virus lymphoproliferative disorder (EBV-LPD) had a median EBV viral load of 445,000 copies/ml (range 3300–5.4 million). Six of seven patients with lymphoma had wide spread organ involvement; 6 patients were treated with Rituxan but only one of them had a sustained response; the rest died of EBV-LPD. Both cases of MDS/MPD were donor derived and fatal. One occurred in a patient transplanted for CLL; the other patient was transplanted for AML. The overall survival for the entire cohort of 53 patients was 55% at two years. The actuarial rate of second malignancy was 19% at 26 months post-transplant (2 year rate of 16%). The rate of donor-derived myeloid disease was 6%. Second malignancy was the leading cause of death, with relapse the second leading cause of death. Neither age, GVHD prophylaxis, HLA matching, nor total nucleated cell dose predicted for a higher rate of second malignancy. There was a trend to a higher risk of second cancer in patients who received an infused CD34+ cell dose of ≤ 1.9 x 105 cells/kg)—(30% vs. 7%, P=0.070). In summary, 1) Second malignancies occur at a high rate after RIC cord blood transplantation; 2) A low infused CD34+ cell dose/kg may be associated with a higher risk of second cancer; 3) Strategies to reduce thymoglobulin dose may be important to reduce the incidence of EBV-LPD; 4) It is important to assess the genetic origin of post-transplant myeloid diseases to establish the risk of donor-derived leukemia.723: Recurrence, Secondary Neoplasia, and Late Complications

Second malignancies after treatment of diffuse large B-cell non-Hodgkin's lymphoma: a GISL cohort study

Improved treatment has increased the life expectancy of patients with non-Hodgkin's lymphoma, but few studies have addressed the issue of second cancer in patients treated for diffuse large B-cell lymphoma. The aims of this study were to determine the incidence and time free of second cancers in this subset of patients. We evaluated a cohort of 1280 patients with diffuse large B-cell lymphoma who were first treated between 1988 and 2003. We utilized the central database of the Gruppo Italiano Studio Linfomi, which includes data on demographics, clinical characteristics, laboratory parameters, treatment and follow-up of all patients with non-Hodgkin's lymphoma enrolled in clinical trials. After a median follow-up of 51 months, 48 patients had developed a second cancer: 13 hematologic malignancies and 35 solid tumors. The overall standardized incidence ratio in our cohort (with a median age of 58 years) matched that of the general Italian population. The incidence ratio of second tumors was age related, and the age groups 20-39 and 40-59 years showed an increased risk. Overall, the cumulative incidence of second cancer was 8.2% at 15 years. A multivariate analysis showed that older age at the time of diagnosis of lymphoma had a negative influence on the time free of second tumors. In our cohort, only young patients showed an increased incidence ratio of second malignancies, while the incidence ratio in patients aged over 59 years matched the incidence in the Italian general population. Demographics, baseline characteristics, laboratory parameters and treatment modalities did not have any significant impact on the incidence ratio of a second cancer.

Increased risk of colon cancer after external radiation therapy for prostate cancer

Radiotherapy can induce second cancers. Controversies still exist regarding the risk of second malignancies after irradiation for prostate cancer. We evaluated the risk of developing colon and rectum cancers after prostate cancer in irradiated and nonirradiated patients. Using data from the population-based Geneva cancer registry, we included in the study all men with prostate cancer diagnosed between 1980 and 1998 who survived at least 5 years after diagnosis. Of the 1,134 patients, 264 were treated with external radiotherapy. Patients were followed for occurrence of colorectal cancer up to 31 December, 2003. We calculated standardized incidence ratios (SIR) using incidence rates for the general population to obtain the expected cancer incidence. The cohort yielded to 3,798 person-years. At the end of follow-up 19 patients had developed a colorectal cancer. Among irradiated patients the SIR for colorectal cancer was 3.4 (95% confidence intervals [CI] 1.7-6.0). Compared to the general population, the risk was significantly higher for colon cancer (SIR = 4.0, 95% CI: 1.8-7.6), but not for rectal cancer (SIR = 2.0, 95% CI: 0.2-7.2). The risk of colon cancer was increased in the period of 5-9 years after diagnosis (SIR = 4.7, 95% CI: 2.0-9.2). The overall SIR of secondary cancer in patients treated with radiotherapy was 1.35 (p = 0.056). Nonirradiated patients did not have any increased risk of rectal or colon cancer. This study shows a significant increase of colon but not rectum cancer after radiotherapy for prostate cancer. The risk of second cancer after irradiation, although probably small, needs nevertheless to be carefully monitored.

Second cancers in patients with male breast cancer: a literature review

The risk of second malignancies among female breast cancer patients has been studied for decades. In contrast, very little is known about second primary tumors in men. Risk factors for breast cancer in men, including genetic, hormonal and environmental factors, provide parallels to the etiology of breast cancer in women. This review considers the literature related to the risk of developing a second cancer in patients with male breast cancer. A systematic review of the literature between 1966 and 2007 was conducted and acceptable articles used for analysis. All retrieved articles were screened to identify any papers that had been missed. Studies were included if they discussed the risk of subsequent malignancy in patients with male breast cancer. Patients with history of male breast cancer have an increased risk of a second ipsilateral, or contralateral breast cancer (standardized incidence ratio 30-110). The risk of subsequent contralateral breast cancer was highest in men under 50 years of age at the time of the diagnosis of the initial cancer. The data on non-breast second primary cancers is diverse. One study has suggested an increased incidence of cancers of the small intestine, prostate, rectum and pancreas, and of non-melanoma skin cancer and myeloid leukaemia. Other investigators did not find an increase in the overall risk of subsequent cancer development in men diagnosed initially with primary breast cancer. Although sarcoma, lung and esophageal cancers are well recognized complications of radiation therapy for female breast cancer, there is no evidence for the association of these cancers following radiation therapy in male breast cancer. Although the incidence of second primary cancer in patients with primary male breast cancer requires further study, male breast cancer survivors should probably undergo periodic screening for the early detection of second breast cancers and other adverse health effects.

Radiotherapy increases risk of secondary cancer in patients with cervical cancer

Radiotherapy increases risk of secondary cancer in patients with cervical cancer

Monte Carlo simulations of neutron spectral fluence, radiation weighting factor and ambient dose equivalent for a passively scattered proton therapy unit

Stray neutron exposures pose a potential risk for the development of secondary cancer in patients receiving proton therapy. However, the behavior of the ambient dose equivalent is not fully understood, including dependences on neutron spectral fluence, radiation weighting factor and proton treatment beam characteristics. The objective of this work, therefore, was to estimate neutron exposures resulting from the use of a passively scattered proton treatment unit. In particular, we studied the characteristics of the neutron spectral fluence, radiation weighting factor and ambient dose equivalent with Monte Carlo simulations. The neutron spectral fluence contained two pronounced peaks, one a low-energy peak with a mode around 1 MeV and one a high-energy peak that ranged from about 10 MeV up to the proton energy. The mean radiation weighting factors varied only slightly, from 8.8 to 10.3, with proton energy and location for a closed-aperture configuration. For unmodulated proton beams stopped in a closed aperture, the ambient dose equivalent from neutrons per therapeutic absorbed dose (H*(10)/D) calculated free-in-air ranged from about 0.3 mSv/Gy for a small scattered field of 100 MeV proton energy to 19 mSv/Gy for a large scattered field of 250 MeV proton energy, revealing strong dependences on proton energy and field size. Comparisons of in-air calculations with in-phantom calculations indicated that the in-air method yielded a conservative estimation of stray neutron radiation exposure for a prostate cancer patient.

Chemoprevention of Second Cancers

"Second cancers" can be thought of in two general categories: (a) those occurring as a consequence of cancer treatment and (b) primary cancers that are thought to develop largely as a consequence of prior lifestyle habits (e.g., chronic smoking, drinking, sun exposures), genetic susceptibility, or interactions of the two. Because there has been limited work on chemoprevention of treatment-related secondary cancers, this minireview will focus on chemoprevention of second cancers with lifestyle/genetic origins. Trials aimed at preventing second cancers in patients with tobacco-related cancers (head and neck, lung), skin cancers, breast cancer, and colorectal adenomatous polyps have been completed with some success. However, one finding that has emerged is that, across several cancer sites, subgroups are found with differential response to the chemopreventive agent. For example, smoking status, alcohol consumption, nutritional status, and host tumor characteristics seem to modify chemopreventive efficacy. Stratum-specific (subgroup) findings may occur by chance, requiring a need for supportive evidence from observational epidemiologic studies of the agent (where available), mechanistic studies, or results of other related trials. Although chemoprevention of second cancers has been realized, it has become increasingly apparent that not all benefit equally. The finding of subgroup effects in completed trials results in the need to consider such subgroup effects in the design of future trials, by either restricting enrollment to particular subgroups (e.g., never or former smokers), or by increasing sample size requirements to allow for variation in response in subgroups in a statistically powerful way.

Risk factors for developing a second upper aerodigestive cancer after radiotherapy with or without chemotherapy in patients with head-and-neck cancers: An exploratory outcomes analysis

The objective was to assess the influence of treatment-related and patient-related factors on the risk of developing a second primary tumor (SPT) of the upper aerodigestive tract (UADT) in patients with locoregionally advanced nonmetastatic carcinomas of the head-and-neck region. The data of 521 patients with a minimum follow-up of 1 year were pooled: 224 patients from the Swiss Group for Clinical Cancer Research (SAKK) 10/94 trial, treated with 1.2 Gy b.i.d. to 74.4 Gy, and randomized to receive or not to receive simultaneous chemotherapy with cisplatin (excluding nasopharyngeal and maxillary sinus carcinomas); and 297 patients from Geneva, all treated with accelerated radiotherapy with concomitant boost to 69.9 Gy and predominantly cisplatin-based concomitant chemotherapy in 33% of patients (including 21 patients with nasopharyngeal carcinomas). An exploratory analysis using competing risk methodology was performed. A total of 65 SPT of the UADT were observed after a median observation time of 4.7 years. The overall risk of experiencing an SPT of the UADT at 10 years in the presence of all other possible events was estimated to be 33%. There were no SPTs after treatment for nasopharyngeal carcinoma. In a multivariate logistic regression analysis, there was no difference in occurrence of SPT at 3 years with respect to the administration of chemotherapy (p = 0.31), age (p = 0.62), performance status (p = 0.61), gender (p = 0.27), presence of nodal disease (p = 0.51), or T stage (p = 0.72). However, patients treated with concomitant boost had fewer SPTs (p = 0.0093). Our data do not suggest that addition of chemotherapy to radiotherapy influences the incidence of second cancers in patients with head-and-neck cancer. The difference in the incidence of SPT between the two radiotherapy schedule groups merits further exploration.

Occurrence of Second Cancers in Patients Treated With Radiotherapy for Rectal Cancer

To analyze the occurrence of second cancers in patients with rectal cancer treated with external radiotherapy (RT) in addition to surgery. The analyses were based on the Uppsala Trial (completed in 1985), with patients randomly assigned to preoperative RT to all stages or postoperative RT for stage II and III cancers, and the Swedish Rectal Cancer Trial (completed in 1990), with patients randomly assigned to preoperative RT or surgery alone. Patients from the trials were matched against the Swedish Cancer Registry. A total of 115 (7%) of the 1,599 patients developed 122 second cancers. More patients treated with RT developed a second cancer (relative risk [RR], 1.85; 95% CI, 1.23 to 2.78). A significant increased risk for second cancers in the RT group was seen in organs within or adjacent to the irradiated volume (RR, 2.04; 95% CI, 1.10 to 3.79) but not outside the irradiated volume (RR, 1.78; 95% CI, 0.97 to 3.27). For the Swedish Rectal Cancer Trial, 20.3% of the RT patients got either a local recurrence or a second cancer, compared with 30.7% of the non-RT patients (RR, 0.55; 95% CI, 0.44 to 0.70). An increased risk of second cancers was found in patients treated with RT in addition to surgery for a rectal cancer, which was mainly explained by an increase in the risk of second cancers in organs within or adjacent to the irradiated volume. However, a favorable effect of radiation seemed to dominate, as shown by the reduced risk of the sum of local recurrences and second cancers.

Outcome following initial external beam radiotherapy in patients with Reese-Ellsworth group Vb retinoblastoma.

To describe patient and ocular outcomes following initial treatment with external beam radiotherapy (EBT) in eyes with Reese-Ellsworth group Vb retinoblastoma. Retrospective case series (from January 1, 1979, to February 28, 2002). The Kaplan-Meier method was used to analyze survival (ocular and patient) and incidence (second cancer) data. Two hundred forty-three patients with 1 or more Reese-Ellsworth group Vb eyes were identified. Of 284 group Vb eyes, 63 (22.2%) initially received EBT, vs 172 (60.6%) that were initially enucleated. Of the 63 radiated group Vb eyes, 31 (49.2%) had no further tumor growth, 26 (41.3%) developed a recurrence, and 8 (12.7%) developed a new tumor. Of the 63 radiated group Vb eyes, 33 (52.4%) developed ocular complications. The ocular survival rate of radiated group Vb eyes was 81.4% at 1 year and 53.4% at 10 years. Twenty-eight radiated group Vb eyes survived to the last follow-up with visual acuity information. Thirteen patients developed second cancers, 11 in the field of radiation. The probability of developing a second cancer following initial EBT for group Vb disease in patients with bilateral disease was 29.7% by 10 years after diagnosis. Survival from second cancers in patients with bilateral disease initially receiving EBT for group Vb disease was 93.6% at 5 years and 52.6% at 18(1/4) years. No patient with unilateral disease developed a second cancer. Deaths due to metastatic retinoblastoma were uncommon. To our knowledge, this is the first study focusing exclusively on group Vb eyes treated initially with EBT, most of which were salvaged with vision. Outcome data provided herein are clinically relevant when choosing treatment options for advanced intraocular retinoblastoma.

Second malignancies following Hodgkin's disease treatment in Tunisia. Retrospective study of 26 cases observed at the institute Salah-Azaïz

To collect second cancers in patients treated for Hodgkin disease (HD) during adolescence and young adulthood at Salah Azaïz Institute of Tunis. We consider as second cancer all tumours other than HD observed in patients after treatment for HD. Twenty-five patients among 614 treated for HD between 1975 and 1991 developed 26 secondary tumours (4.2%). There were 17 males and eight females (sex ratio 2:1). Mean age at the diagnosis of HD was 32.5 years (12-56). HD was stage II (eight cases), stage III (14) and stage IV in three. The first treatment was combined chemotherapy and radiotherapy in 22 cases and only chemotherapy in three cases (stage IV). Radiotherapy was delivered with Cobalt 60 by large fields. Mean dose was 41.3 Gy (2 Gy/fraction in 21 and 3.3 in one). Chemotherapy was MOPP (13), MOPP and vinblastine (four), MOPP-ABVD (five), ABVD (two) and vinblastine only in one. Mean delay of second tumours was 114.5 months (40-276). There was five acute myeloid leukaemia, two digestive non-Hodgkin lymphomas, five nodal high-grade lymphomas, three breast cancers (one in man associated with thyroid cancer), five lung cancers (three non-small cell and two of small cell type), two gastric tumours and one rectal cancer, one synovialosarcoma of the knee and one malignant Schwannoma of the neck. Median survival was 12.5 months (2-48). Twenty-one patients died and four are still alive with 8, 12, 24 and 48 months of follow-up. Second cancer risk after treatment for HD is not low. Risk factors and preventive strategies are discussed.

Risk of Second Cancer in Patients With Hairy Cell Leukemia: Long-Term Follow-Up

PURPOSE: The purpose of the present study was to assess the risk of second cancers in patients with hairy cell leukemia (HCL). PATIENTS AND METHODS: We investigated the incidence of additional cancers in those patients registered in the nationwide registry of the Italian Cooperative Group for the Study of HCL, asking the cooperating centers for additional information on initial and subsequent therapies and on time and type of second malignancies, if they developed. Here we report the final results of this survey, consisting of 54 cases of second malignancies (excluding nine cases of epithelial skin cancer) which developed in 54 patients of 1,022 with adequate follow-up. RESULTS: The cumulative risk of development of a second cancer was 5%, 10%, and 14% at 5, 10, and 15 years, respectively. The incidence of second malignancies was not significantly higher than the expected rate (standardized incidence ratio [SIR], 1.01; 95% confidence interval [CI], 0.74 to 1.33; P = 1.0). However, the SIR of non-Hodgkin’s lymphoma in the entire cohort was 5.3 (95% CI, 1.9 to 11.5). Second malignancies occurred in eight (4.7%) of 386 patients who never received interferon (IFN), nine (5.9%) of 495 patients treated with IFN at the time of diagnosis, and seven (6.9%) of 102 patients who received IFN as second-line therapy. These differences were not statistically significant. Analysis of the separate calendar periods did not reveal any particular trends with respect to variations in SIR. CONCLUSION: The present study does not support the suspicion that patients with HCL are at increased risk of additional second malignancies, although the incidence of lymphoid neoplasms was significantly higher than expected. In addition, our data indicate that IFN therapy did not exert an oncogenic effect in such patients.

Risk of second cancer in patients with hairy cell leukemia: long-term follow-up.

The purpose of the present study was to assess the risk of second cancers in patients with hairy cell leukemia (HCL). We investigated the incidence of additional cancers in those patients registered in the nationwide registry of the Italian Cooperative Group for the Study of HCL, asking the cooperating centers for additional information on initial and subsequent therapies and on time and type of second malignancies, if they developed. Here we report the final results of this survey, consisting of 54 cases of second malignancies (excluding nine cases of epithelial skin cancer) which developed in 54 patients of 1,022 with adequate follow-up. The cumulative risk of development of a second cancer was 5%, 10%, and 14% at 5, 10, and 15 years, respectively. The incidence of second malignancies was not significantly higher than the expected rate (standardized incidence ratio [SIR], 1.01; 95% confidence interval [CI], 0.74 to 1.33; P = 1.0). However, the SIR of non-Hodgkin's lymphoma in the entire cohort was 5.3 (95% CI, 1.9 to 11.5). Second malignancies occurred in eight (4.7%) of 386 patients who never received interferon (IFN), nine (5.9%) of 495 patients treated with IFN at the time of diagnosis, and seven (6.9%) of 102 patients who received IFN as second-line therapy. These differences were not statistically significant. Analysis of the separate calendar periods did not reveal any particular trends with respect to variations in SIR. The present study does not support the suspicion that patients with HCL are at increased risk of additional second malignancies, although the incidence of lymphoid neoplasms was significantly higher than expected. In addition, our data indicate that IFN therapy did not exert an oncogenic effect in such patients.

Risk of second cancers in patients with colorectal carcinoids.

It is often stated that patients with colorectal carcinoid tumors have an increased risk of developing other malignancies. However, this risk has not been conclusively documented. A comprehensive evaluation is needed to more thoroughly assess the risk of second cancers in patients with colorectal carcinoids. A search of the National Cancer Institute Surveillance, Epidemiology, and End Result database from 1973 to 1996 revealed 2,086 patients with colorectal carcinoids. This subset of patients was examined for occurrence of second cancers. The observed incidence of cancer for each site was compared with the expected incidence based on the gender-adjusted and age-adjusted cancer rates in the remaining Surveillance, Epidemiology, and End Result file. A Poisson distribution probability was used to determine the significance of these comparisons. Patients with colorectal carcinoids had an increased rate of cancer in the colon and rectum (P < 0.001), small bowel (P < 0.001), esophagus/stomach (P = 0.02), lung/bronchus (P < 0.001), urinary tract (P = 0.005), and prostate (P < 0.001), when compared with a control population. Most of the gastrointestinal tract cancers were synchronous cancers, whereas lesions outside the gastrointestinal tract were most commonly metachronous tumors. A significantly increased risk of synchronous colorectal, small-bowel, gastric, and esophageal cancers and metachronous lung, prostate, and urinary tract neoplasms is clearly demonstrated. After the diagnosis of colorectal carcinoid tumors, patients should undergo appropriate screening and surveillance for cancer at these sites.

Increased Risk of Secondary Cancers in Patients with Primary Cutaneous T Cell Lymphoma

As putative etiologic factors of primary cutaneous T cell lymphomas may have a general cancerogenic effect, we wanted to assess the risk of secondary malignancies in 319 patients diagnosed with histopathologically verified cutaneous T cell lymphomas and reported to the Finnish Cancer Registry during the years 1953-95. Standardized incidence ratios were defined as the ratio of observed to expected numbers of cases. To obtain the expected numbers of cancer, age-, sex-, and period-specific Finnish incidence rates were applied to the appropriate person-years under observation. Ninety-five percent confidence intervals were calculated assuming a Poisson distribution. For the whole period, we detected 36 secondary cancers whereas 26 were expected (standardized incidence ratios 1.4, 95% confidence intervals 1.0-1.9). The overall risk of lung cancer was significantly increased (standardized incidence ratio was 2.7, 95% confidence intervals were 1.4-4.8); and in particular small-cell lung cancer showed high standardized incidence ratios (standardized incidence ratio was 8.5, 95% confidence intervals were 2.8-20). Also, the risk of lymphomas was elevated (standardized incidence ratios for Hodgkin and non-Hodgkin lymphomas combined were 7.0, 95% confidence intervals were 1.9-18). The incidence of other cancers was similar to the national ratios. An increased risk of secondary cancers and in particular small-cell cancer of the lung and lymphomas among patients with primary cutaneous T cell lymphoma is demonstrated. In clinical practice, lung cancer and lymphomas must be kept in mind when following up patients with cutaneous T cell lymphomas.

Second malignancy in hairy cell leukaemia: no evidence of increased incidence after treatment with interferon alpha.

The last decade has seen a dramatic improvement in prognosis of hairy cell leukaemia (HCL) but concern has emerged with regard to the incidence of second malignancy. A recent report found an 18.8% incidence of second cancers and suggested a possible role for alpha-interferon (IFN) in their pathogenesis. We reviewed our larger series of 200 patients with HCL. We found second malignancies in 8 cases (4.0%), all but one of whom had received IFN. However, when compared to age- and sex- matched population data this represents no increase in relative risk of second cancer in patients with HCL and provides no evidence of a role for IFN in the pathogenesis of these second malignancies.

Smoking, Treatment for Hodgkin's Disease, and Subsequent Lung Cancer Risk

Smoking, Treatment for Hodgkin's Disease, and Subsequent Lung Cancer Risk

Incidence of second cancers in patients treated for Hodgkin's disease.

Numerous studies of treatment for Hodgkin's disease have demonstrated large increases in the incidence of leukemia in the early years following chemotherapy, although the duration of effect and the specific agents involved are not well understood. Also, some, but not all, studies have indicated that the incidence of certain solid tumors increases following treatment for Hodgkin's disease. We studied the association between treatment for Hodgkin's disease and the incidence of second cancers. We conducted a study within a cohort that included 10,472 patients from 14 cancer centers in the United States and Canada who were first diagnosed as having Hodgkin's disease at some point from 1940 through 1987. Discounting the 1st year after diagnosis, the average length of follow-up was 7.1 years per subject. We observed 122 leukemias and 438 solid tumors. The relative risk (RR) of leukemia following chemotherapy, compared with no chemotherapy, was 14 (95% confidence interval [CI] = 5.6-35). Increased risks of leukemia were observed after treatment with chlorambucil (RR = 2.0; 95% CI = 1.1-3.6), procarbazine (RR = 4.9; 95% CI = 2.6-9.1), vinblastine (RR = 1.7; 95% CI = 1.1-2.8), and a group of rarely used drugs that included methotrexate, vindesine, etoposide, and 22 others (RR = 3.8; 95% CI = 1.9-7.4). RRs were also estimated for various combinations of drugs, including MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) (RR = 5.9; 95% CI = 2.9-12) and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (RR = 1.5; 95% CI = 0.7-3.4). The RR of leukemia associated with splenectomy was 1.6 (95% CI = 1.0-2.5). The RR of solid tumors following chemotherapy was 1.4 (95% CI = 1.1-1.8). For the group of rarely used drugs, the RR of solid tumors was 3.1 (95% CI = 1.7-5.8). Chemotherapy was associated with an increased risk of cancers of the bones, joints, articular cartilage, and soft tissues (RR = 6.0; 95% CI = 1.7-20), and cancers of the female genital system (RR = 1.8; 95% CI = 1.1-3.2). In patients followed for 10 or more years after radiotherapy, increased risks were found for cancers of the respiratory system and intrathoracic organs (RR = 2.7; 95% CI = 1.1-6.8) and for cancers of the female genital system (RR = 2.4; 95% CI = 1.1-5.4). Procarbazine, chlorambucil, and vinblastine are associated with increased leukemia risk. Combination drug regimens have leukemogenic effects estimated as the product of RRs for individual drugs. Chemotherapy and radiotherapy increase the risk of selected solid tumors, and the effect of chemotherapy on solid tumor risk is weaker than the leukemogenic effect. Without doubt, the benefits of treatment of Hodgkin's disease outweigh the risk of a subsequent malignancy, but data on the carcinogenic effects of radiation and drugs beyond 10 years after treatment continue to be sparse, and future analyses should be directed at long-term survivors.