Occurrence Of Second Neoplasms Research Articles

The challenge of survivors of gynecological carcinomas: a retrospective study on occurrence of second tumors.

To clarify the epidemiologic characteristics and risk of other tumors in survivors of gynecological tumors. This is a retrospective study based on the Surveillance, Epidemiology, and End Results database (SEER). The morbidity of other malignant tumors in patients with gynecological cancer was 8.07%. The most common subsequent tumors are breast, lung, colorectal, thyroid, and bladder cancers. Taking the incidence rate of the general population as reference, the second tumor with the highest relative risk in patients with cervical cancer is vulvar cancer. Bladder cancer is the second tumor with the highest relative risk value both in patients with corpus and ovarian cancer. The median period from the diagnosis of the initial tumor to the diagnosis of the second tumor was 5 years. Most patients with other tumors following gynecological cancer showed worse prognosis than patients with gynecological tumors only. However, thyroid cancer following ovarian cancer is a protective factor in survival. Patients with gynecological tumors have a significantly higher risk of malignant tumors in other systems compared to ordinary population. It is necessary to be vigilant against subsequent high-risk tumors and tumors with poor prognosis within 5 years of initial diagnosis.

Occurrence of symptomatic meningioma as a second neoplasm in patients with differentiated thyroid cancer treated with radioiodine

Occurrence of second tumors has been seen in patients with papillary and follicular thyroid cancer. We studied the occurrence of meningioma as a second neoplasm in patients with differentiated thyroid cancer treated with radioiodine at our institution.

Analysis of Toxicity and Efficacy of Subcutaneous Cladribine at Reduced or Standard Doses (Five Versus Seven Consecutive Days) In Patients with Hairy Cell Leukemia (HCL) In the ICGHCL2004 Protocol by the Italian Cooperative Group on Hcl

AbstractAbstract 701 Introduction:Hairy cell leukemia (HCL) is generally responsive to intravenous Cladribine (iv2CdA). Subcutaneous Cladribine (sc2CdA) is an alternative route with 100% bioavailability. In indolent non-Hodgkin lymphomas other than HCL, at the dose of 0.7 mg/kg/cycle, efficacy of sc2CdA is similar to iv2CdA and reduction to 0.5 mg/kg/cycle determines equivalent efficacy and lower toxicity. Aims:In a national multicentre clinical trial (protocol EudraCT code: ICGHCL 2004), we prospectively evaluated toxicity and efficacy of sc2CdA given 0.1mg/kg/die for 5 (total dose 0.5 mg/kg, arm A) or for 7 consecutive days (total dose 0.7 mg/kg, arm B) as a single course in classic HCL requiring first treatment. Method:Clinical data and diagnostic samples were collected from all patients for central revision of classical HCL diagnosis (WHO criteria) and for molecular analyses at the University of Siena, prior to study entry. Early grade 3–4 toxicity was assessed on days 7 to 30 after treatment, according to the 2003 NCI/CTCAE v3 criteria and occurrence of second tumors was assessed at every subsequent follow-up. Enpoints of sc2CdA efficacy were response to treatment, treatment free interval (TFI), relapse free survival (RFS), time to second tumor (TTST) and overall survival (OS). Responses to treatment were assessed on days 60 and 180 after treatment and defined according to the 1987 Consensus criteria. Complete Remissions (CR) and Partial Remissions (PR) were rated as beneficial responses (CR/PR), while minor Responses (mR) and No Responses (NR) were rated as treatment failures (mR/NR). TFI was measured as the time elapsed from sc2CdA initiation to second treatment because of new progression or failure to sc2CdA. RFS was measured in patients with a CR/PR from treatment inititation to relapse. OS was measured from sc2CdA initiation to death for any cause. Result:of 156 patients screened centrally, 148 scored as classical HCL and entered the study. Gender (male total 116/148, 78,4%; arm A: 62/77, 80,5% vs arm B: 54/71, 76,1%), age (total: median age 52 years, range 30–83; arm A: median 56, range 30–83; arm B: median 51, range 33–82), clinical and laboratory parameters prior to treatment (including spleen, hemoglobin, platelet, leucocyte and hairy cell counts) were equally balanced in the two arms. Dose reduction was required in no patients from arm A and in 2 patients from arm B due to concurrent infection. Overall hematological toxicity was no different among the two treatment arms. Requirement of platelet transfusions (total 7/148, 4,7%; arm A: 2/77, 2,6% vs arm B: 5/71, 7%), red blood cell transfusion (total 32/148; 21,6%, arm A: 15/77, 19,5% vs arm B: 17/71, 23,9%), or G-CSF (total 102/148; 68,9%, arm A: 55/77, 71,4% vs arm B: 47/71, 66,2%) was no different among the two arms. However, a significantly higher non hematological toxicity (total 28/148; 18,9%, arm A: 9/77, 11,7% vs arm B: 19/71, 26,8%) was observed in arm B (p=.019). Non haematological toxicity was mainly represented by infections or FUO (total 25/148; 16,9%) that were significantly more frequent in arm B (arm A: 8/77, 10,4% vs arm B: 17/71, 23,9%, p=.028). Higher prevalence of toxicity resulted in a higher hospitalization rate in arm B than in arm A (total 29/148; 19,6%, arm A: 9/77, 11,7% vs arm B: 20/71, 28,2%, p=.012) and one early death was experienced because of lung aspergillosis in arm B. Onehundred-forty patients (94,6%) had a beneficial response (101 CR, 68,2%; 39 PR, 26,4%) and 8 (5,4%) failed treatment (5 mR, 3,4%; 3 NR, 2%). Responses were equivalent in the two arms, with 72/77 (93,5%) beneficial responses (49/77 CR, 63,6%; 23/77 PR, 29,9%; 4/77 mR, 5,2% and 1/77 NR, 1,3%) in arm A versus 68/71 (95,8%) beneficial responses in arm B (52/71 CR, 73,2%; 16/71 PR, 22,5%; 1/71 mR, 1,4%; 2/71 NR, 2,8%). After a median follow-up of 36 months (range 12–66), 5 year TFI, RFS, TTST and OS were 67%, 71% 87% and 94%, respectively. Causes of late death were 2 cardiac events and 3 second tumors. No differences of TFI, RFS, TTST and OS were observed in the 2 arms of treatment. Conclusion:The present data indicate that overall activity of sc2CdA is similar to iv2CdA (Cheson, 1998). Furthermore, this study indicates that sc2CdA given at 25% reduced doses (0.5 mg/kg) has equivalent activity and significantly lower toxicity than sc2CdA at standard doses (0.7 mg/kg). The reduced infection rates and hospitalization rates of sc2CdA have important pharmaco-economic implications. Disclosures:No relevant conflicts of interest to declare.

Prostate cancer as a first and second cancer: effect of family history

Background:Diagnosis with prostate cancer has been reported to increase the risk of subsequent tumours. However, specific data on individuals with a parental history are not available so far.Methods:On the basis of the nationwide Swedish Family-Cancer Database including 18,207 primary invasive prostate cancers, standardised incidence ratios (SIRs) were used to estimate the relative risks of subsequent tumours after prostate cancer in the general population and among individuals with a parental history of cancer.Results:A significantly increased SIR of colorectal cancer was found among prostate cancer patients with a parental history of colorectal cancer (2.26, 11 cases). The SIRs of parental concordant (same site) tumours after prostate cancer were also increased for urinary bladder cancer (4.42, 4 cases) and chronic lymphoid leukaemia (38.0, 2 cases).Conclusion:A higher than additive and multiplicative interaction was observed between the individual history of prostate cancer and parental history of colorectal and urinary bladder cancers, although the number of cases did not permit the rejection of any interaction model. The results suggest that the occurrence of second tumours, for example bladder after prostate or prostate after bladder tumours, is mostly related to shared genetic and non-genetic risk factors rather than treatment of first cancer.

Long-Term Follow-up of Patients Affected by Relapsed Lymphomas Receiving Reduced-Intensity Conditioning (RIC) Regimen Followed by Allogeneic Stem Cell Transplantation (Allo-SCT): An Update of the Phase II Study of the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO)

Several groups have reported the results of Allo-SCT following a RIC regimen in relapsed and refractory lymphomas. However, the long-term efficacy of this strategy is still unknown. We report herein the results of a prospective multicenter phase II trial at median follow-up of 5 years. A total of 194 relapsed/refractory lymphomas received the same RIC regimen (thiotepa, cyclophosphamide and fludarabine) followed by Allo-SCT from sibling donors. Histologies were non-Hodgkin's lymphomas (NHL) [indolent (LG-NHL, n=68), including follicular lymphoma (FL, n=29), chronic lymphocytic leukemia (CLL, n=35), other (n=4); aggressive (HG-NHL, n=87), including B-cell phenotype (n=43), T-cell phenotype (n=28), mantle cell lymphoma (MCL, n=16)] and Hodgkin's lymphoma (HL, n=39). 133 (68%) of 194 patients (pts) had chemosensitive disease and 100 (52%) of 194 failed a previous autologous transplantation. Median follow-up was 60 months (range, 15–113). At last follow-up, 116 pts are alive (59%) and 78 died from any cause [n=47 for disease progression, n= 30 for non-relapse mortality (NRM), n=1 not assessable]. The 5-year overall survival (OS) and progression-free survival (PFS) were 62% and 70% for LG-NHL, 61% and 59% for HG-NHL, and 42% and 19% for HL, respectively. The median time to relapse was 7 (range, 2–30), 4.5 (range, 1.6–33), and 5.5 (range, 0.4–42) months for LG-NHL, HG-NHL, and HL respectively. Pts with chemosensitive disease at Allo-SCT had 5-year OS and PFS of 69% and 61%, while those with refractory disease had 5-year OS and PFS of 35% and 45%, respectively. Status of disease at Allo-SCT influenced significantly long-term outcome in HG-NHL and HL [chemosensitive versus chemorefractory: 73% versus 32% (p<0.001) for HG-NHL; 64% versus 0% (p<0.002) for HL] but not in LG-NHL [chemosensitive versus chemorefractory: 65% versus 56% (p=0.43)], probably related to a stronger graft-versus-lymphoma effect in LG-NHL. Although, the 5-year PFS was significantly different between FL and CLL (85% versus 58%, p=0.04), the 5-year OS was not (71% versus 56%, p=0.13). The OS and PFS were not significantly different between aggressive lymphoma of B- and T-cell phenotype [5 year OS: 67% versus 55% (p= 0.51); 5 year PFS: 63% versus 57% (p=0.45)], respectively. Additionally, the comparison of a subgroup of pts receiving Rituximab within 6 months prior to Allo-SCT (n=38) with an homogeneous group of pts who did not receive the antibody (n=60) did not influence the outcome. Overall, 30 pts died of transplant-related causes (n=13 infections, n=12 GVHD, n=1 VOD, n=2 MOF and n=2 second tumor) at median follow-up of 6 months (range, 0.8 to 60) with a 5-year cumulative incidence of 15%. The incidence of acute and chronic GVHD were 34% and 55%, respectively. Interestingly, only 27 of 116 (23%) pts are still receiving immune suppressive therapy. The incidence of second tumors was 2% in the pts surviving more than 6 months after Allo-SCT (n=2 alive, n=2 death). In conclusion, analysis of our series with a median 5-year follow-up shows that: (i) pts with relapsed lymphomas could achieve long-term remission and are probably cured; (ii) the occurrence of second tumors deserves further attention.

Secondary neoplasms following tumor and leukemia therapy in childhood. Report of 64 cases

64 second neoplasms, occurring after therapy of malignant tumors or leukaemia in childhood, came to light in the course of a collaborative group investigation. Most frequent initial diseases were acute lymphoblastic leukaemia (n = 19), Morbus Hodgkin (n = 9), and retinoblastoma (n = 8), whereas osteosarcoma (n = 13), cancer of the thyroid (n = 10) and acute non-lymphoblastic leukaemia (n = 8) were predominant among the second malignant neoplasms. In 36 of 50 irradiated children there was a clear relationship between the localisation of the second neoplasm and the earlier irradiated zone. In other cases, in particular in children with retinoblastoma as initial disease or neurofibromatosis, genetic influences on the origin of the second neoplasms come into question. The preponderance of Morbus Hodgkin after acute lymphoblastic leukaemia (n = 7) must be regarded as extraordinary; in 6 of the 7 children the second neoplasm appeared after a very short interval. A distinct effect of previous treatment with cytostatics on the occurrence of second neoplasms was not seen. The differing time intervals between the occurrence of the first and the second neoplasms in the separate subgroups point toward heterogenous causes being involved in the development of second neoplasms.

Classification tree analysis of second neoplasms in survivors of childhood cancer

BackgroundReports on childhood cancer survivors estimated cumulative probability of developing secondary neoplasms vary from 3,3% to 25% at 25 years from diagnosis, and the risk of developing another cancer to several times greater than in the general population.MethodsIn our retrospective study, we have used the classification tree multivariate method on a group of 849 first cancer survivors, to identify childhood cancer patients with the greatest risk for development of secondary neoplasms.ResultsIn observed group of patients, 34 develop secondary neoplasm after treatment of primary cancer. Analysis of parameters present at the treatment of first cancer, exposed two groups of patients at the special risk for secondary neoplasm. First are female patients treated for Hodgkin's disease at the age between 10 and 15 years, whose treatment included radiotherapy. Second group at special risk were male patients with acute lymphoblastic leukemia who were treated at the age between 4,6 and 6,6 years of age.ConclusionThe risk groups identified in our study are similar to the results of studies that used more conventional approaches. Usefulness of our approach in study of occurrence of second neoplasms should be confirmed in larger sample study, but user friendly presentation of results makes it attractive for further studies.

High incidence of meningioma in cranial irradiated survivors of childhood acute lymphoblastic leukemia

Most survivors of childhood acute lymphoblastic leukemia (ALL) and T-cell lymphoma (T-NHL) treated before 1990 received cranial radiation. This study assessed the occurrence of second tumors in irradiated and non-irradiated survivors. Two hundred and ten survivors of ALL and T-NHL were treated between 1974 and 1997 by several protocols. Imaging (MRI, CT) was performed every 3-6 years in 76/88 irradiated and 74/122 non-irradiated patients for the last 20 years. From January 1998 through 2004, meningiomas were detected in 16 survivors (8 female, 8 male) at age 20-39 years (median 28.7); 15 were asymptomatic. Cranial imaging done 2-8 years previously in 11 revealed no abnormalities. Fifteen had been diagnosed with ALL or T-NHL 10-29 years earlier (median 21) and received cranial irradiation (24 Gy in 14) at age 2-14 years (median 7.6). Fifteen tumors arose in the convexity. Three patients had multiple lesions. Complete resection was performed in 12 patients, with one complication. One patient had a recurrence, and four with small tumors are under surveillance. Only one low-grade glioma and two basal-cell carcinomas were found. Only one of the 74 non-irradiated patients (median follow-up 14 years) developed meningioma. The Kaplan-Meier estimate of incidence of meningioma was 14.8+/-7.6 at 20 years. Survivors of childhood ALL treated with cranial radiation require prolonged surveillance because of a high incidence of late meningiomas. Early detection, when the tumor is still small, facilitates resection and may reduce complications.

Long-Term Results of Conventional Radiotherapy versus Accelerated Hyperfractionated Radiotherapy versus Concomitant Radiotherapy and Chemotherapy in Locoregionally Advanced Carcinoma of the Oropharynx

To compare conventional fractionation (CF) radiation therapy (RT), arm A, versus a split-course accelerated hyperfractionated schedule (S-AHF), arm B, versus CFRT plus concomitant chemotherapy (CT), arm C, in terms of five-year survival and toxicity for squamous cell tumors of the oropharynx. Between January 1993 and June 1998, 192 previously untreated patients with stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were enrolled in a multicenter randomized phase III trial (ORO 93-01). In arms A and C, 66 to 70 Gy in 33 to 35 fractions was administered five days a week for six and a half to seven weeks. In arm B, the dose delivered was 64 to 67.2 Gy in two fractions of 1.6 Gy every day, five days a week, with a planned two-week split at 38.4 Gy. In arm C the CT regimen consisted of three cycles of carboplatin and 5-fluorouracil (CBDCA 75 mg/m2 on days 1 to 4 and 5-FU 1000 mg/m2 i.v. on days 1 to 4 every 28 days). No statistically significant difference was found in five-year overall survival (P = 0.39): 21% for arm A, 21% for arm B, and 40% for arm C. Similarly, there was no statistically significant difference in terms of five-year relapse-free survival: 15% for arm A, 17% for arm B, and 36% for arm C. There was a slight trend towards better five-year locoregional control (P = 0.07) for the combined arm: patients without locoregional relapse were 48% in arm C, 21% in arm A and 18% in arm B. Locoregional control was significantly better when arm C was compared with arms A and B combined (P = 0.02; arm A+B 20%; arm C 48%). Distant metastases were fairly balanced in the three arms (A: 14; B: 9; C: 11), with a tendency towards more frequent isolated distant metastasis development in arm C (8 of 11 [72%] versus 7 of 23 [30%] in arms A+B). Five-year second-tumor-free survival was 85%. The 13 second tumors were equally distributed and were mainly correlated with tobacco and alcohol consumption (five lung, two esophagus, two oral cavity, one larynx, one pancreas, one hepatocarcinoma, one myeloma). Arm C showed slightly more G3+ late side effects involving subcutaneous tissues and mucosa, although significant late sequelae were relatively uncommon and the mucosal side effects were mostly transient. The occurrence of persistent G3 xerostomia was comparable in the three treatment arms. The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance, but combined treatment almost doubled the five-year overall survival, relapse-free survival and locoregional control rate. Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy. The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death.

Increased Prevalence of Colorectal Adenomas in Women with Breast Cancer

Background: The frequency of colorectal adenomas and carcinomas was investigated in a large cohort of women with breast cancer in comparison with matched controls, since data on the occurrence of second tumors in women with breast cancer is controversial. Design: In a cohort study, 188 consecutive women (median age 57 years) with primary breast cancer and 376 age-matched women who served as controls were examined by total colonoscopy. Breast cancer patients and controls were compared for the frequency of colorectal adenomas and carcinomas. Results: Women with breast cancer showed a higher risk of colorectal adenomas than controls (14.9 vs. 9.3%, p = 0.047, OR 1.7, 95% CI 1.0–2.9). This increased prevalence resulted primarily from an increased prevalence in the age group 65–85 (31 vs. 10%, p = 0.004, OR 3.8, 95% CI 1.6–9.3). Colorectal carcinomas were found infrequently in both groups (2 in each group). Women with breast cancer receiving anti-estrogen therapy showed a trend towards a lower risk of adenomas compared to women without anti-estrogen therapy (3.7 vs. 17.2%, p = 0.053, OR 0.16, 95% CI 0.0–1.1). Conclusions: Women with breast cancer above the age of 65 years have an increased risk of colorectal adenomas compared to women without breast cancer. Women with a diagnosis of breast cancer should especially be encouraged to participate in colorectal cancer-screening programs which, in most countries, call for screening of all average-risk individuals over the age of 50 years.

No evidence of association of methylenetetrahydrofolate reductase polymorphism with occurrence of second neoplasms after treatment of childhood leukemia

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been associated not only with the risk for acute lymphoblastic leukemia (ALL) in adults and children, but also with increased methotrexate toxicity. The present study aimed to investigate whether MTHFR polymorphisms modify the risk for development of secondary malignancies in children treated for ALL with protocols that included high-dose methotrexate. MTHFR genotypes were determined in DNA samples isolated from archived bone marrow smears of 15 patients with a second malignancy and a matched control group of 30 patients who did not developed a second malignancy after the treatment for ALL. The frequencies of MTHFR C677T and A1298C genotypes in all patients were: C677T: CC 40%, CT 46.7% and TT 13.3% and A1298C: AA 46.7%, AC 44.4% and CC 8.9%. The relative risk for second malignancy was not significantly increased in ALL patients having at least one polymorphic C667T [odds ratio (OR) 1.51; 95% confidence interval (CI) 0.43-5.31] or one polymorphic A1298C allele (OR 1; 95% CI 0.29?-?3.46). Our study suggests that MTHFR polymorphisms are not associated with increased risk of second cancer in children treated with high-dose methotrexate.

Second neoplasms after treatment of childhood cancer in Slovenia.

The number of long time survivors of childhood cancer treatment is constantly increasing over the last decades as a result of advances in diagnosis and treatment. The occurrence of second neoplasms is one of most serious late effects observed in cancer survivors. The risk of secondary neoplasm was studied in a cohort of 1,577 patients treated for childhood cancer registered in the Cancer Registry of Slovenia (CRS) between 1961 and 2000. The time at risk was defined from the date of diagnosis of first malignancy to the time of death or the end of the study. The most frequent primary malignancies were: acute leukemia 28.5%, central nervous system (CNS) tumors 21.3%, and lymphomas 16.6%. Median observation time was 7.8 years. Forty-eight patients developed second neoplasms. CNS tumors, acute leukemias, and thyroid carcinoma were most frequent second neoplasms. The cumulative risk for second neoplasm in the entire cohort was 0.06% at 5 years, 5.1% at 15 years, and 12.6% at 25 years after diagnosis of first cancer. The overall survival after second neoplasm was 65% 10 years after the diagnosis of second neoplasm. Patients after treatment of childhood cancer are at special risk for subsequent neoplasms and long-term follow-up is mandatory.

Oral squamous cell carcinoma following treatment of acute lymphoblastic leukaemia

With substantially increased survival after most paediatric cancers over the past decades have come the late sequelae of treatment. Of all late complications of treatment, second malignancies are generally considered to be the most serious. We report on a 20-year-old man with an oral squamous cell carcinoma 17 years after initial chemotherapy and irradiation for acute lymphoblastic leukaemia. Although occurrence of the oral malignancy in this patient could have been treatment-related, one should keep in mind that the occurrence of second tumours may also be based on a shared genetic aetiology.

Occurrence of second neoplasms in chronic lymphocytic leukemia experience at Padua Hospital between 1979 and 1991

We report a retrospective study about the incidence of second neoplasms (SN) in patients affected by chronic lymphocytic leukemia (CLL) admitted to Padua Hospital between 1989 and 1991, comparing data with those of a similar population. We examined the records of 212 patients, finding in 19 of them 22 second neoplasms; the most common kind was lung cancer. There was an increased incidence of SN, without statistic significance if compared with all sites of cancers in the general population, especially during the first 2 years from the diagnosis of CLL. In accordance with the majority of authors, there is an unknown connection between the two diseases, but certainly independent of chemotherapy with alkylating agents.

Decreasing risk of leukemia with prolonged follow-up after chemotherapy and radiotherapy for Hodgkin's disease.

Acute nonlymphocytic leukemia is a recognized complication of combined chemotherapy and radiation treatment of patients with Hodgkin's disease. Previous studies have suggested that the risk of leukemia in these patients increases with time after treatment. We analyzed the occurrence of second neoplasms among 192 patients with Hodgkin's disease who were followed for a median of over 15 years. We originally planned to identify prospectively the morphologic changes in bone marrow that precede the development of acute leukemia. All 63 patients consenting to bone marrow aspiration had normal marrow morphology, and no case of acute leukemia occurred more than 11 years after treatment. Actuarial analysis revealed that the peak onset of leukemia-related complications was between three and nine years after first treatment. We conclude that there appears to be a period of increased risk in patients treated with chemotherapy and radiation, after which the risk of secondary leukemia decreases. Patients surviving for more than 11 years after treatment appear to be at no increased risk of acute leukemia.

Occurrence of second tumors in man after anticancer drug treatment

Occurrence of second tumors in man after anticancer drug treatment

Multiple malignancies in patients with primary carcinomas of the head and neck

Eight hundred and twenty-five patients with primary carcinomas of the head and neck area were studied. Of these, there were 54 individuals with multiple primary neoplasms. Synchronous lesions occurred in 19 patients while nonsynchronous lesions occurred in 35. The frequency of occurrence of second neoplasms was 6.5%, which nearly doubles that of previously recorded series. A conclusion which can be made from this study is that, as long as the carcinogenic agent (alcohol and/or tobacco) continues to be present, the patient will continue to be affected.

Secondary Neoplasms in Multiple Myeloma

To the Editor.— The coexistence of multiple myeloma and another cancer in the same patient has been reported on several occasions. 1 The occurrence of second neoplasms in patients treated with melphalan for multiple myeloma (236:1609, 1976) is a rare but well-recognized phenomenon. The most frequent second neoplasm is acute myelocytic leukemia. 2 It is far from clear whether the melphalan is causally related to the development of acute leukemia or whether this disease represents the natural evolution of multiple myeloma hitherto obscured by early deaths. I agree with the editorial (236:1612, 1976) that such reports ... should alert physicians and stimulate a careful examination of all patients who receive melphalan to determine if multiple primary neoplasia is occurring in these patients and to assess its suppressive effect on tumor growth in those patients who do not have multiple myeloma or some other condition that may impair immunocompetence. There could develop