Second Primary Cancers In Patients Research Articles

The incidence and risk of second primary cancers in patients with nasopharyngeal carcinoma: a population-based study in Taiwan over a 25-year period (1979–2003)

BackgroundVery few reports are available on the incidence and risk of second primary cancers in nasopharyngeal carcinoma (NPC) cases, and most of these are single-institution reviews with relatively small case numbers and short follow-up. Patients and methodsA population-based study was conducted. We quantified standardized incidence ratios (SIRs) and cumulative incidence of second cancers among 23639 individuals with initial diagnoses of NPC. ResultsWe found a 24% increased risk of second cancers in NPC patients compared with the general population [SIR=1.24, 95% confidence interval 1.15–1.33]. Elevated SIRs were observed in the following second primary cancers: oral/pharyngeal, salivary gland, sarcoma, skin and leukemia/lymphoma. The cumulative incidence >10 years was 3.26%. The risk was higher in younger patients, especially those <40 years old. After diagnosis of second cancers, the median survival time was 1.7 years. ConclusionsThis is the largest population-based study to date from a high-incidence area. We found that NPC is associated with an increased risk of second malignancies, which had a negative impact on the survival of patients who survived NPC.

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.

Surgical Outcome of Synchronous Second Primary Cancer in Patients with Gastric Cancer

PurposeIn order to improve the likelihood of curative and safe gastric surgery, this study investigated the clinical features and surgical outcomes of gastric cancer with a synchronous cancer.Patients and MethodsThe clinicopathological data of 10,090 gastric cancer patients at Samsung Medical Center from September 1994 to December 2006 were retrospectively analyzed. Of them, 90 patients with gastric cancer and a synchronous second primary cancer underwent simultaneous surgery for gastric cancer and second primary cancer. The clinicopathological characteristics of the patients, surgical outcome, and prognosis were examined.ResultsThe most common synchronous second primary cancer was colorectal cancer (37 patients), followed by hepatocellular carcinoma (13 patients), renal cell carcinoma (11 patients), and pancreatic carcinoma (5 patients). The incidence of a second primary cancer in the gastric cancer patients was higher than the incidence in the general population. Stage I gastric cancer patients had more synchronous cancers than stage II patients (59 vs. 31). Postoperative complications were encountered in 7 patients. Four patients underwent reoperation. Two patients died from hepatic failure and leakage of esophagojejunal anastomosis. The 5-year survival rate of stage I and II gastric cancer was 61% and 39%, respectively.ConclusionSince gastric cancer patients with a synchronous second primary cancer are not rare, the possibility of synchronous cancers in gastric cancer patients should be considered. The prognosis of early stage gastric cancer patients with a synchronous second primary cancer was influenced more by the presence of the second primary cancer than by the gastric cancer itself.

Chemoprevention of bladder cancer

Chemoprevention of cancer can be accomplished using primary, secondary, or tertiary strategies. Tertiary chemoprevention has been the predominant approach for bladder cancer and addresses the need for preventing the occurrence of second primary cancers in patients who have previously been treated for cancer. Because non–muscle-invasive bladder cancer is associated with a high risk of recurrence, tertiary chemoprevention has been studied in this population. Although considerable preclinical data has demonstrated the feasibility of this approach, application to the clinical setting has met with limited success. This review discusses chemoprevention of bladder cancer and focuses on the drugs used in chemoprevention investigations and clinical study design.

Colonic second primary cancers in patients with index tumours of the head and neck.

Colonic second primary cancers in patients with index tumours of the head and neck.

Chemoprevention of Head and Neck Cancer With Retinoids

To determine whether isotretinoin (or 13-cis-retinoic acid) decreases the risk of second primary cancers in patients previously treated for cure of head and neck squamous cell carcinoma. Randomized, double-blind, placebo-controlled trial. Two head and neck multidisciplinary cancer clinics in university teaching hospitals taking cases from 4 to 5 million people in Queensland, Australia, combined to enter appropriate patients into this trial. One hundred fifty-one patients with their first head and neck squamous cell carcinoma treated with high expectation for cure and living close by. They were randomized into 3 arms to receive 3 years of treatment. Patients took isotretinoin at a high dose (1.0 mg/kg per day) or a moderate dose (0.5 mg/kg per day) or placebo. Group 1 took the high dose for 1 year and then the moderate dose for 2 years. Group 2 took the moderate dose for 3 years. Group 3 took placebo for 3 years. The diagnosis of a second primary malignancy of the head and neck, lung, or bladder was regarded as the end point signifying failure of therapy. Issues of drug adverse effect profile and impact on survival were measured. There was no significant difference in the occurrence of second primary disease (P = .90), the recurrence of primary disease (P = .70), or disease-free time (P = .80) between the treatment and nontreatment arms. Numbers were too small to find differences in survival. With evidence that retinoid treatment adversely affects survival of lung cancer and with this drug not significantly decreasing the incidence of second primary tumors of head and neck squamous cell carcinoma, the use of this drug in head and neck cancer patients for second cancer prophylaxis is not indicated.

Effective follow-up for recurrence or a second primary cancer in patients with early gastric cancer

Patients with early gastric cancer have an excellent prognosis with low rates of recurrence, but may have an increased risk of developing a second primary cancer. Because the number of early gastric cancers has increased, clarification of both recurrences and second primary cancers is important for the development of effective postoperative follow-up programmes. Data on 1070 patients with early gastric cancer were analysed retrospectively with respect to the clinicopathological features of both recurrence and second primary cancers after surgical treatment. Multivariate analysis showed that lymph node metastasis and older age were independent risk factors for recurrence of early gastric cancer. The incidence of second primary cancers was 5.0 per cent; lung and colorectal cancers were detected most frequently, followed by cancers in the oesophagus, breast and remnant stomach. Clinicopathological features of patients with early gastric cancer can be used to identify those most at risk of developing either recurrence or a second primary cancer.

The risk of other primary cancer in patients with uveal melanoma: a retrospective cohort study of a Canadian population

Background: The incidence of second primary malignant tumours has doubled during the last 2 decades.These tumours now represent the sixth most common group of cancers. Many authors have described the presence of multiple primary cancers in patients with uveal melanoma. However, no studies have been performed using Canadian data.The purpose of this study was to describe the occurrence of other primary cancers diagnosed before or after uveal melanoma and to calculate the incidence of subsequent primary cancer in a Canadian cohort with uveal melanoma.Methods: We conducted a retrospective study of a cohort of patients with uveal melanoma diagnosed between 1990 and 2002 at a university-affiliated centre in Montreal. We reviewed medical records to identify patients in whom other, unrelated primary malignant disease had been diagnosed.We used the standardized incidence ratio to calculate the risk of development of a second, unrelated cancer following the diagnosis of uveal melanoma.Results: A total of 129 cases of uveal melanoma were diagnosed. Eighteen patients (14%) also had a diagnosis of an unrelated primary cancer. In nine patients the other cancer had been diagnosed first, and in nine patients the other tumour had been diagnosed after the uveal melanoma. There was no increased risk of development of any particular form of cancer studied for females or males.Interpretation: In our Canadian cohort, statistical analysis showed no increased risk of a second cancer, overall or by organ site, in male or female patients with uveal melanoma.As uveal melanoma is a rare type of cancer, analyses of a much larger cohort may be needed to accurately estimate the risk of development of a second primary cancer in patients with uveal melanoma.

Features of Second Primary Cancer in Patients with Gastric Cancer

Background: In order to improve the prognosis of gastric cancer patients, the timely identification of second primary cancers is considered to be a crucial clinical problem. Methods: We analyzed the clinicopathological data of 2,250 patients with gastric cancer with regard to both synchronous and metachronous second primary cancers. Results: Of 2,250 patients, 95 (4.2%) had a second primary cancer. Both colorectal and lung cancer were frequently detected, followed by cancer in the liver, esophagus and breast. Regarding the time of detection for such second cancers, 65% of colorectal cancers were detected synchronously, while more than 80% of lung cancers were detected metachronously. The prognosis of gastric cancer patients with a second primary cancer was more negatively influenced by a second primary cancer than by a primary gastric cancer. Conclusion: Since gastric cancer patients may develop synchronous and metachronous second cancers in other organs, effective preoperative and postoperative diagnostic modalities both for second primary cancers, as well as for the recurrence of gastric cancer, need to be developed.

The utility of tolonium chloride rinse in the diagnosis of recurrent or second primary cancers in patients with prior upper aerodigestive tract cancer.

The clinical utility of tolonium chloride rinse was compared with unaided visual examination alone in the diagnosis of oral carcinoma in patients previously treated for carcinoma of the upper aerodigestive tract. A total of 668 patients were enrolled in this multicenter study. At each site, an oral clinical visual examination was completed by one investigator followed by tolonium chloride rinse and examination by a second investigator blinded to the examination findings of the first investigator. If a lesion was considered suspicious (urgent biopsy required at the first visit), the lesion was biopsied after tolonium chloride rinsing. Patients with lesions characterized at the first visit as not suspicious (biopsy not urgent) or that stained with tolonium chloride were asked to return for a second visit. At the second visit, any residual lesion or lesions that retained tolonium chloride were biopsied. A total of 96 biopsies was performed in 81 of the 668 patients (12.1%), of which 30 (31.3%) were diagnosed histologically as carcinoma/carcinoma in situ (CIS) and the remainder as inflammation (31.3%), keratosis (26.6%), dysplasia (21.9%), ulcer (2.1%), other (3.1%), or no abnormality (1.0%). Of the 30 lesions with the diagnosis of carcinoma/CIS, 12 (sensitivity 40.0%) were considered to be clinically suspicious (CS+), whereas 29 (sensitivity 96.7%) retained tolonium chloride (p =.0002). The predictive values of a positive test for clinical examination and tolonium chloride staining were similar (36.4% vs 32.6%; p =.5871), indicating that the greater sensitivity of tolonium chloride was not associated with an excessive number of unnecessary biopsies (false positives). Tolonium chloride rinse is more sensitive than clinical examination alone in detecting lesions that might be found on biopsy to be carcinoma or CIS. The increased sensitivity is largely attributed to lesions that stain but were not detected clinically on visual examination.

Efficacy of intense screening and treatment for synchronous second primary cancers in patients with esophageal cancer.

The optimum management of esophageal cancers with synchronous second primary cancer (SPC) has not been determined. The aim of this study was to evaluate the efficacy of intense screening and treatment for esophageal cancers with synchronous SPC. Between 1981 and 1997, 1479 patients with esophageal cancers were screened for synchronous SPC during the process of initial staging. Radical treatment was recommended for esophageal cancer and synchronous SPC in cases for whom both cancers were curable. Treatment results for esophageal cancer patients with or without synchronous SPC were compared. Among 1479 patients, 155 (10.5%) were found to have 166 synchronous SPC. Primary sites included the stomach in 65, the head and neck in 44, the colon/rectum in 27, the lung in 14 and other sites in 16 patients. Clinical stages of synchronous SPC were stage I in 41%, stage II in 20%, stage III in 25% and stage IV in 14%. The 5-year overall survival rates by clinical stages of esophageal cancers (stage 0, I, II, III, IV) in patients with synchronous SPC were 51% (95% CI, 23-78%), 43% (95% CI, 18-68%), 11% (95% CI, 0-22%), 14% (95% CI, 0-28%) and 12% (95% CI, 1-22%), respectively. The 5-year overall survival rate for patients with or without synchronous SPC were 20% (95% CI, 13-28%) and 32% (95% CI, 29-35%), respectively. No significant difference was observed between both groups (p = 0.2562). Intense screening and treatment may be justifiable in the light of the high detection rate of curable SPC and the reasonable survival of patients with synchronous SPC. However, a prospective study including cost-benefit analysis is needed to provide the evidence to justify the intense screening and treatment.

Risk of second primary malignancies in patients with cutaneous melanoma

In several studies an increased risk for development of breast cancer, malignant lymphoma and neoplasms of the kidney as second primary cancers in patients with cutaneous melanomas was discussed. To determine the risk for development of second primary neoplasms in patients with cutaneous melanomas. A prospective study was performed between 1977 and 1992 to evaluate the occurrence of second primary malignancies in 4597 patients (2083 men, 2514 women) with invasive cutaneous melanomas, diagnosed and treated at the Department of Dermatology and Allergology, Ludwig-Maximilians-University, Munich, Germany. During a median follow-up of 7.2 years, 296 of 4597 patients (6.4%) developed one or more neoplasms at the time of or subsequent to the diagnosis of the first cutaneous melanoma. More than half of these patients developed one or more further melanomas (152, 3.3%). Cancers of the breast, prostate, colon, rectum and kidney occurred less frequently. Statistical calculations revealed a 33.8-fold increased risk for the development of a second melanoma in the entire group [relative risk 38.5 for men (95% CI, 30.4-48.1), 29.0 for women (95% CI, 22.0-37.5)]. Moreover, a significantly increased risk for the development of kidney carcinoma in men was found [relative risk 3.5 (95%, CI, 1.4-7.2)]. Thorough follow-up and skin examination in patients with cutaneous melanomas is recommended for early detection of other primary melanomas. Furthermore, ultrasound examinations routinely performed in melanoma patients for the detection of melanoma metastases may also be of value for early detection of kidney carcinomas in male patients.

Multiple primary cancers of the colon, breast and skin (melanoma) as models for polygenic cancers.

To assess the role of family history in the development of multiple primary cancer, the Swedish Family-Cancer Database was used to analyze second primary cancer in patients born in 1935 to 1996 with an initial primary cancer of the colon, breast and skin (melanoma) by familial cancer in first-degree relatives. Standardized incidence ratios (SIRs) were calculated from site-, sex- and age-specific rates for all persons (offspring) born in 1935 to 1996. Familial risk (SIR) was calculated for the first and second primary cancers in offspring. A Poisson regression analysis was also performed to assess the risk factors for occurrence of second primary cancer. The familial proportion of multiple primary cancers was 29.0% (9/31) for colon, 16.3% (122/747) for female breast and 14.5% (17/117) for melanoma. Compared with all offspring, patients with family history were at a much higher and significantly increased risk for subsequent primary cancer at colon (SIR = 59.1), skin (SIR = 48.2) and female breast (SIR = 7.9). The corresponding SIRs in patients without family history were 13.8, 10.5 and 5.2 at the three sites. The ratios for incidence of second primary to first primary were highest when diagnosis age was less than 40 years. A Poisson regression analysis showed that family history was one of the major risk factors for occurrence of multiple primary cancers at colon, breast and skin. The high risk of second cancer, even in the absence of family history, would be consistent with a polygenic model of carcinogenesis.

Expression of RARalpha and RARbeta in human oral potentially malignant and neoplastic lesions.

Retinoids reverse potentially malignant lesions and inhibit the development of second primary cancers in patients with head-and-neck cancer. Many of the effects of retinoids result from modulation of gene expression by 2 distinct classes of nuclear receptor, RARs and RXRs; alterations in their expression can lead to tumorigenesis. To determine whether aberrations in expression of the receptors are related to the development of betel- and tobacco-related oral cancer, we used specific monoclonal antibodies against RARalpha and RARbeta to detect expression of these proteins in 30 histopathologically normal tissues, 45 potentially malignant lesions (leukoplakia) with histological evidence of either hyperplasia (31 cases) or dysplasia (14 cases) and 64 oral squamous-cell carcinomas (SCCs) by immunohistochemistry. Of the 30 normal oral tissues analysed, 8 cases showed detectable levels of RARalpha protein, while 10 cases did not show detectable RARbeta immunoreactivity. Immunostaining for RARalpha protein was observed in 12/31 (39%) hyperplastic lesions, 6/14 (43%) dysplastic lesions and 43/64 (67%) oral SCCs. Expression of RARalpha in oral SCC was significantly associated with the histological differentiation status of tumours (p = 0.016). In contrast, lack of detectable immunoreactivity was observed in 19/31 (61%) hyperplastic lesions, 8/14 (57%) dysplastic lesions and 21/64 (33%) oral SCCs. The hallmark of the study was the significant increase in RARalpha immunopositivity in oral SCCs compared to normal tissue (p = 0.0005) and hyperplastic lesions (p = 0.016). One intriguing feature was the significant decrease in RARbeta immunopositivity in hyperplastic lesions compared with normal oral mucosa (p = 0.05) as well as in oral SCCs compared with normal tissues (p = 0.0008).

Gastric cancer

Prostate brachytherapy may be associated with a lower risk of radiation-induced second primary cancer (SPC) as a significantly smaller volume of normal tissue is irradiated when compared with external beam techniques. Limited data are available as it has been a routine treatment option for less than 20 years. This study identified cases of SPC in patients who underwent I-125 prostate brachytherapy as monotherapy in a single institution.SPC incidence was retrieved by conducting a UK cancer registry search (Northern and Yorkshire Cancer Registry and Information Service) for 1805 consecutive patients with localised prostate cancer who received monotherapy with I-125 brachytherapy from 1995 to 2006 at a single public hospital. Of 1730 UK residents, the completeness of the registry match was 91% (1574 patients). The mean age at treatment (interquartile range) of the cohort was 63 (58–68) years with 1100 patients (70%) over the age of 60 years at treatment. The median (range) follow-up was 8 (6–10) years with 487 patients (31%) having 10 years or more.In total, 170 patients (10.8%) were diagnosed with second primaries (1 year or more after implant); 20 of these were bladder and 10 rectal cancers. The 10 year cumulative incidences were 14.6, 1 and 0.84% for any second malignancy, bladder and rectal cancer, respectively. Only the standardised incidence rate (SIR) for bladder cancer was higher at 1.54 (95% confidence interval 0.96–2.46) compared with the general population. The SIR for bladder cancer was higher in the first few years after treatment, suggesting that the increased incidence of bladder cancer is due to increased urological surveillance.Overall, the incidence of SPC after I-125 is comparable with other published data with no significant excess more than 5 years from treatment. Mortality secondary to SPC of the bladder or rectum is unusual.

Risk of multiple primary cancers in prostate cancer patients in the Detroit metropolitan area: a retrospective cohort study.

Patterns of excess risk for second primary cancers (SPC) in prostate cancer patients have been observed for urinary bladder, other sites in the urinary tract, and hematolymphopoietic tissues in several, but not all, previously reported cohort studies. The risk of SPC was evaluated in 9,794 Detroit metropolitan-area men originally diagnosed with carcinoma of the prostate during 1973-1982. The cohort was assembled using Detroit Surveillance, Epidemiology, and End Results (SEER) Registry data and followed until December 31, 1993. The observed number of SPC of all sites was similar to the expected number in the cohort. A significant excess of invasive SPC of the urinary bladder [Standardized incidence ratio (SIR) = 1.57; 95% CI, 1.34-1.83] was observed in this cohort, but after excluding the first 2 months after prostate cancer diagnosis, the excess (SIR = 1.06) was no longer statistically significant. The cumulative proportion of patients with prostate cancer who developed bladder cancer during a follow-up interval of 20 years was 5.5% (95% CI, 4.1-6.9%). The patients who received first-course radiation treatment were observed to be at increased risk for bladder SPC (all stages; SIR = 1.49; 95% CI, 1.07-2.02) when compared to the Detroit-area male population. These results underscore the importance of continuing medical surveillance for urinary bladder second primary cancers in patients with prostate cancer, but are reassuring in that the magnitude of relative and absolute risks does not suggest deterring adverse effects of radiation treatment or intrinsic risks for neoplasms in other organs or tissues.

Second primary cancers in breast cancer patients in Slovenia.

Data from the Cancer Registry of Slovenia were used in a cohort study to determine whether the incidence of second primary cancers in patients with first primary breast cancer differs from the incidence expected in the general population. Special interest was given to long-term survivors. The expected numbers of second primary cancers were calculated by multiplying the number of appropriate person-years at risk by the corresponding age- and calendar-period-specific cancer incidence rates for women in Slovenia. The risk of a second primary cancer was expressed as the standardized incidence ratio (SIR). Of the 8,917 patients newly diagnosed in the period 1961-85 and followed-up to the end of 1994, 547 (6.2 percent) developed second primary cancers, whereas 410 (4.7 percent) were expected (SIR = 1.3, 95 percent confidence interval [CI] = 1.2-1.4). The risk was higher among younger patients. In long-term survivors, the risk was increased significantly for second primary cancer of the breast (SIR = 1.4, CI = 1.1-1.7), lung cancer (SIR = 1.6, CI = 1.1-2.3), melanoma (SIR = 2.7, CI = 1.5-4.4) and non-melanoma skin cancers(SIR = 2.0, CI = 1.6-2.4), corpus uteri cancer(SIR = 1.6, CI = 1.2-2.1), ovarian cancer(SIR = 2.3, CI = 1.7-3.0), and thyroid cancer (SIR = 2.5, CI = 1.2-4.6). Our results confirm the findings of several cohort studies carried out in Europe, the United States, and Japan, indicating that breast cancer patients should be monitored carefully for the occurrence of second primary cancers.

Can Breast Reconstruction with Gel-Filled Silicone Implants Increase the Risk of Death and Second Primary Cancer in Patients Treated by Mastectomy for Breast Cancer?

An increased risk of cancer and autoimmune disease associated with gel-filled silicone implants has been suggested recently, but these possible detrimental effects have not been adequately studied in patients with breast cancer. In order to evaluate these effects, we have studied 146 patients with breast cancer treated by mastectomy at the Gustave Roussy Cancer Institute between 1965 and 1983 and who received a gel-filled silicone implant for immediate or delayed breast reconstruction between 1976 and 1984. These patients were compared with 146 matched controls with breast cancer who were treated in the same center by mastectomy without breast reconstruction and were matched for age at diagnosis (within 10 years), year of diagnosis (within 3 years), stage, histologic type of the tumor, histopathologic grade, and nodal status. The relative risks of death, relapse, and second primary cancer were estimated by means of the Cox proportional hazards model stratified on age at diagnosis. The risks of distant metastasis and death due to breast cancer were significantly lower in the breast reconstruction group than in the control group. The risks of local recurrence, second breast cancer, and second primary cancer in another site than the breast were not significantly different between the two groups of patients. Our results do not support the hypothesis of a detrimental effect of gel-filled silicone implants either in the course of breast cancer or in the risk of death due to other diseases.

Can breast reconstruction with gel-filled silicone implant increase the risk of death and second primary cancer in patients treated by mastectomy for breast cancer?

Can breast reconstruction with gel-filled silicone implant increase the risk of death and second primary cancer in patients treated by mastectomy for breast cancer?

Second primary cancers in patients with carcinoma of the lip

The occurrence of second primary cancers in patients with lip cancer was evaluated in order to test certain etiologic hypotheses. All cases of lip cancer reported to the Finnish Cancer Registry in 1953-74 (3303 men, 320 women) were followed up for a second (or third) primary cancer through the files of the Registry either to death or to 31 December 1974 (a total of 25 510 person-years). The expected numbers of cases were calculated on the basis of the incidence rates specific for sex, age, time and residence (urban or rural) in Finland. A higher than expected risk of cancer was found among both urban and rural male lip cancer patients; among women the observed number of new primary cancers did not differ from that expected. A significant excess risk among males was noted for cancers of the lung and larynx (rural patients) and for non-melanomatous skin cancer in locations other than the head and neck (urban patients). The association of cancers of the lip, lung and larynx found earlier on a geographic level supports the hypothesis that tobacco smoking is a common risk factor in these cancers. The differences in the relative risks between urban and rural patients, however, suggest that the risk factors in lip cancer in urban areas might be partially different from those prevalent in the rural population. The results do not support the hypothesis that sunlight is an important risk factor in lip cancer.