Introduction
Multiple primary malignancy (MPM) in a cancer patient is not a new or a very rare
occurrence. The diagnosis of a second or a third primary is very often not easy to
arrive at due to the possibility of recurrent or secondary lesions from the first
malignancy confounding the issue. This can lead to delay in initiation of appropriate
treatment and can affect overall prognosis and survival. The most common presentation
of MPMs is as dual malignancies.[1]
[2]
The concept of MPMs in one individual was first described by Billroth in 1889.[3] In 1921, Owen published a report highlighting the possible causes of MPMs wherein
they found 4.7% of cases of multiple growths in 3000 cases of malignancy.[4] Warren and Gates [5] published the first literature about multiple cancers in 1932 and described the
following salient points for their diagnoses: (a) each of the tumors should be malignant
with proven histology, (b) they should be histologically distinct from each other,
and (c) the exclusion of metastasis should always be made. In 1977, Moertel [5]
[6] further refined the concept and classified multiple primary cancers and multicenter
cancers into various groups based on their tissue and organ of origin [Table 1].
Table 1
Classification of multiple primary malignant nconlasms
|
Category
|
Description
|
|
I
|
Multiple primary malignant neoplasms of multicenter origin
|
|
A. The same tissue and organ
|
|
B. A common, contiguous tissue shared by different organs
|
|
C. The same tissue in bilaterally paired organs
|
|
II
|
Multiple primary malignant neoplasms of different tissues or organs
|
|
III
|
Multiple primary neoplasms of multicenter origin plus a lesion (s) of different tissue
or organ
|
MPMs can be divided into synchronous or metachronous on the basis of the time interval
between the diagnosis of the two primaries. As per Moertel et al.,[7] synchronous or “simultaneous” malignancies are those primary tumors which occur
in the same patient within 6 months of each other, whereas metachronous or “interval”
malignancies are those that occur in the same patient separated by a period that is
>6 months. Although this definition of synchronous and metachronous tumors is the
one most commonly used, it is not the only one and other researchers have used 12
months and other varying time intervals to define the temporal relation between MPMs.
Indian data on MPMs are limited to a few case reports or case series,[8]
[9]
[10] with limited or no follow-up. Collection of long-term data with adequate follow-up
and survival analysis is crucial to understanding the natural history of patients
with MPMs in our country. In this retrospective analysis, we aim to report the incidence
of dual malignancy seen in our practice and the demographic distribution, the patient
and disease characteristics, and the management offered in such cases.
Materials and Methods
This is a descriptive study of retrospectively collected data from the cancer registry
of a tertiary cancer hospital. Records of patients registered and treated at our center
over a period of 4 years from January 2013 to December 2016 were perused. All patients
who were found to have histologically proven MPMs were included in the study. Localized
or disseminated recurrence of the same histological tumor was not included in the
study.
Various demographic details such as patient’s age at the time of each tumor diagnoses,
sex, any relevant family history and history of tobacco usage were recorded. Similarly,
disease details such as site of tumor, stage at presentation, histology, and time
interval between the two diagnoses were also noted. If the two primary malignancies
were diagnosed within 6 months of each other, they were labeled as synchronous, and
if the time interval between their diagnoses was > 6 months, the second neoplasm was
categorized as a metachronous tumor. Among synchronous tumors, the one that was diagnosed
earlier was deemed to be the first primary and the one detected subsequently was classified
as the second primary.
Complete treatment details including surgery, radiotherapy, and systemic therapy were
also registered. Only patients with a recorded follow-up period of 1 year from the
diagnosis of second primary were included in the study. Patients who did not follow
up in the hospital were included only if they or their caregiver could be contacted
via telephone and disease status at 1 year from diagnosis could be recorded. The patients
were divided into four groups as given below:
-
Alive and disease free – Patient alive at 1 year with no evidence of residual disease
-
Alive with stable disease – Patient alive at 1 year with residual disease that has
either decreased partially or not increased in spread or volume since diagnosis
-
Alive with progressive disease – Patient alive at 1 year with residual disease that
has increased in spread or volume since diagnosis
-
Dead – Patient who has died within 1 year of diagnosis.
Survival of patients with metachronous and synchronous tumors at 1 year was depicted
using Kaplan–Meier graphs, and the survival probability between the two was compared
using the log-rank test. Similar graphs were also generated to show the survival of
different stages of the second primary cancer. All the collected data were organized
in a tabular form, and the patterns of demographic, disease, treatment, and survival
data were analyzed and reported.
Results
The list of patients included in the study is given in [Table 2]. A total of 29 cases of dual malignancies were found and included in our study comprising
0.74% of a total of 3879 cancer patients seen over a period of 4 years. There was
a clear female predominance with 65.5% (19) of the patients being women. Interestingly,
this female predominance was limited to the age group below 60 years, while the male
sex was much more common in the age group above 60 years [Figure 1].
Table 2
Details of patients diagnosed with dual malignancies at our center over a period of
4 years (2013-2016)
|
Age* (years)
|
Sex
|
First priman' with stage**
|
Treatment
|
Syn/Meta*** (time interval)
|
Second primary with stage**
|
Treatment
|
Status at one year from diagnosis of 2nd primary
|
Remarks
|
|
*Age of diagnosis of second primary; **A11 cancers have been staged as per AJCC 7th
edition (2010); ***Syn – Synchronous (time interval <6 months); Meta – Metachronous
(time interval >6 months). NACT – Neoadjuvant chemotherapy; IP – Ifosfamide + cisplatin;
Adjt – Adjuvant; CT – Chemotherapy; Ca- Carcinoma; NSCLC – Non-small cell lung carcinoma;
Adenoca – Adenocarcinoma; Pall – Palliative; RT – Radiotherapy; fx – Fractions; PC
– Paclitaxel + carboplatin, SD – Stable disease; TAH – Total abdominal hysterectomy;
BSO – Bilateral salpingo-oophorectomy ; ILC – Invasive lobular carcinoma, CMF – Cyclophosphamide
+ methotrexate + 5-flurouracil; EBRT – External beam radiotherapy, IDC – Invasive
ductal carcinoma; MRM – Modified radical mastectomy; AC – Doxorubicin + cyclophosphamide;
HT – Hormonal therapy; PD – Progressive disease; CCRT – Concurrent chemoradiotherapy;
LND – Lymph node dissection; ICBT – Intracavitary brachytherapy; DC – Docetaxel +
carboplatin, GC – Gemcitabine + carboplatin, PR – Partial response, BT – Brachytherapy;
PSA – Pro static-specific antigen; B/L – Bilateral; ADT – Androgen deprivation therapy;
AIM – Doxorubicin + ifosfamide + mesna; CapeOx – Capecitabine + oxaliplatin, 5FU/LV-5
– Fluorouracil + leucovorin, DLBCL – Diffuse large B-cell lymphoma; R-CHOP -rituximab
+ cyclophosphamide + doxorubicin + vincristine + prednisolone; IFRT – Involved field
radiotherapy; RAI – Radioactive iodine therapy; LAR – Low anterior resection; PFS
– Pyriform sinus; WLE – Wide local excision
|
|
29
|
Female
|
Osteosarcoma mandible T1N0M0G3 – Stage IIA
|
NACT (3×IP) + surgery (hemimandibulectomy) + Adjt CT (3×IP)
|
Meta (5 years)
|
Ca lung (NSCLC) Adenoca T3N2M1 – Stage IV
|
Pall RT to brain (30 Gy/10fx) + PallCT (6×PC) + geftinib
|
Alive with SD
|
|
|
72
|
Female
|
Ca ovary Papillary serous Adenoca T3cNlM0 – Stage IV
|
Surgery (TAH + BSO + cytoreduction) + Adjt CT (6×PC)
|
Meta (4 years)
|
Ca colon Adenoca T3N0M0 – Stage IIA
|
Surgery (hemicolectomy) + Adjt CT (capecitabine)
|
Alive with PD
|
|
|
55
|
Female
|
Ca breast ILC T2N2M0 - Stage IIIA
|
Surgery (Rt MRM) + Adjt CT (6×CMF) + EBRT (45 Gy/20 fx) + HT (tamoxifen)
|
Meta (3 years)
|
Renal cell Ca Clear cell Ca T3aN0Ml - Stage IV
|
Surgery (cytoreductive nephrectomy) + pazopanib
|
Alive with PD
|
|
|
45
|
Female
|
Ca breast IDC T2N3M0 - Stage IIIC
|
Surgery (Lt MRM) + Adjt CT(6×CMF)+ EBRT (45 Gy/20 fx)
|
Meta (23 years)
|
Ca ovary Papillary serous Adenoca T3cNlMl - Stage IV
|
Surgery (cytoreduction) + CT (6×PC)
|
Alive with SD (on CT)
|
Family history of Ca breast (sister)
|
|
70
|
Female
|
Ca Breast IDC T3N1M0 - Stage IIIA
|
Surgery (Lt MRM) + Adjt CT(4×AC+12× paclitaxel)+EBRT (50 Gy/25 fx)+HT (letrozol)
|
Meta (2 years)
|
Ca pancreas Adenoca T4N0M0 - Stage III
|
CCRT (50.4 Gy/28 fx + capecitabine)
|
Died at 8 months
|
Tobacco user (Khaini and Pan) × 35 years
|
|
54
|
Female
|
Ca endometrium endometroid Adenoca pT3N2M0 - Stage IIIC2
|
Surgery (TAH + BSO + LND) + Adjt CT (6×PC) + EBRT (50.4 Gy/28 fx) + ICBT (6 Gy×2 fx)
|
Syn (3 months)
|
Ca thyroid Papillary T1N0M0 - Stage I
|
Surgery (total thyroidectomy)
|
Alive with PD (lung meta)
|
|
|
61
|
Female
|
Ca ovary Serous papillary Adenoca pT3aN0M0 - Stage IIIA
|
Surgery (TAH + BSO + cytoreduction) + Adjt CT (6×DC)
|
Meta (3 years)
|
Ca cervix (vaginal vault) squamous cell Ca T2bNlMl - Stage IVB
|
Pall EBRT (50 Gy/25 fx) + Pall CT (2×PC + 4 ×GC)
|
Alive with SD (PR)
|
|
|
36
|
Female
|
Ca breast IDC + medullary Ca T2N1M0 - Stage IIB
|
Surgery (Rt MRM) + Adjt CT(4×AC + 12×Pacli) + EBRT (45 Gy/20 fx) + HT (tamoxifen)
|
Meta (3 years)
|
Ca ovary Papillary serous Adenoca T1cNOMO - Stage 1C
|
Surgery (TAH + BSO + LND) + Adjt CT (6×PC)
|
Alive and disease free
|
Family history of Ca lung (father)
|
|
37
|
Female
|
Ca cervix Adenoca T3bN0M0 - Stage IIIB
|
CCRT (50.4/28 fx + 5 × cisplatin) + ICBT (7Gy×3fx)
|
Syn (5 months)
|
Ca ovary Mucinous Adenoca T3cNlMl - Stage IIIC
|
Surgery (TAH + BSO + LND + omentectomy) + Adjt CT (6×PC)
|
Alive with PD (abdominal deposits)
|
|
|
74
|
Male
|
Ca prostate Adenoca, Gleason - 7 T3N0Mlb, PSA 82 ng/ml - Stage IV
|
Surgery (B/L orchiectomy) + 12×zoledronate
|
Syn (3 months)
|
Ca stomach Adenoca T3N2M1 - Stage IV
|
Diagnostic laparotomy + Pall CT (6×PC)
|
Died at 8 months
|
Tobacco user (bidi) × 50 years
|
|
63
|
Male
|
Ca prostate Adenoca, Gleason - 7 T2N0Mlb, PSA-44 ng/ml Stage IV
|
Surgery (B/L orchiectomy) + ADT (bicalutamide) + Pall CT (6×doce + 12×zoledronate)
+ Pall EBRT to pelvis and spine (30 Gy/10 fx)
|
Meta (3 years)
|
Ca pancreas neuroendocrine tumor T4N0M1 Gd2-Stage IV
|
Best supportive care
|
Died at 2 months
|
|
|
47
|
Female
|
Ca breast IDC T2N1M0 - Stage IIB
|
Surgery (Rt MRM) + Adjt CT (6×TAC) + EBRT (50 Gy/25 fx)
|
Syn (5 months)
|
Ca lung (NSCLC) Adenoca T3N2M1 - Stage IV
|
Pall CT (6×pemetrexed + cisplatin) + geftinib
|
Alive with SD (PR) (or geftinib)
|
|
|
68
|
Male
|
Ca parotid mucoepidermoid Ca T2N0M0 - Stage II
|
Surgery (Lt parotidectomy + LND) + Adjt EBRT (60 Gy/30 fx)
|
Meta (3 years)
|
Soft-tissue sarcoma thigh Hemangiopericytoma T2bN0Ml - Stage IV
|
Pall CT (6×AIM) + Pall RT (30 Gy/10 fx)
|
Alive with SD
|
|
|
66
|
Male
|
Ca hypopharynx squamous cell Ca T3N1M0 - Stage III
|
CCRT(70Gy/35fx+5 × cisplatin)
|
Meta (8 years)
|
Ca lung (NSCLC) squamous cell Ca T4N2Mlb - Stage IV
|
Best supportive care
|
Died at 1 month
|
Tobacco user (bidi× 35 years)
|
|
65
|
Female
|
Ca Breast IDC T4N1M0 - Stage IIIB
|
Surgery (Lt MRM) + Adjt CT(2×AC) Patient defaulted after that
|
Meta (6 years)
|
Ca rectum Adenoca (signet ring cell) T3N2M1 - Stage IV
|
Surgery (diversion colostomy) + Pall CT (2×capeOx) -defaulted
|
Alive with PD
|
Tobacco user (cigarette) × 20 years
|
|
67
|
Female
|
Ca colon Adenoca T3N1M0 - Stage IIIB
|
Surgery (Lt hemicolectomy) + Adjt CT (5FU/LVX6)
|
Syn (4 months)
|
Ca breast IDC T2N2M0 - Stage IIIA
|
NACT (4AC) + surgery (Lt MRM) + Adjt CT(12x Pacli) + EBRT (45 Gy/20 fx)
|
Alive and disease-free
|
|
|
69
|
Male
|
Ca lung (NSCLC) Adenoca T3N2M0 - Stage IIIA
|
Unwilling for treatment
|
Syn (0 months)
|
Ca esophagus Squamous cell Ca T2N2M0 - Stage IIIA
|
Unwilling for treatment
|
Died at 3 months
|
Tobacco user (bidi) × 40 years Fd cancer
|
|
66
|
Female
|
Ca esophagus (cervical) Squamous cell Ca T3N1M0 - Stage IIIA
|
CCRT(50.4Gy/28fx + 5 ×PC)
|
Syn (3 months)
|
Ca Thyroid Follicular T1N0M0 - Stage I
|
Surgery (sub-total thyroidectomy)
|
Alive and disease-free
|
Tobacco User (bidi) × 20 years
|
|
50
|
Female
|
Parotid lymphoma DLBCL Stage IIIE
|
Surgery (Lt parotidectomy) + CT (6×R-CHOP) + IFRT (30Gy/15fx)
|
Meta (3 years)
|
Ca thyroid Follicular T2N0M0 - Stage II
|
Surgery (total thyroidectomy) + RAI
|
Alive and disease-free
|
|
|
55
|
Female
|
Ca esophagus Squamous cell Ca T3N2M0 - Stage IIIB
|
CCRT (50.4 Gy/28 fx + 5 × PC)
|
Meta (3 years)
|
Ca breast IDC T2N0M0 - Stage IIA
|
Surgery (Rt MRM) + Adjt CT (4 × AC + 12×Pacli) + tamoxifen
|
Alive and disease free
|
|
|
69
|
Male
|
Ca prostate Adenoca, Gleason - 9 T2N0Mlb, PSA-28 ng/ml - Stage IV
|
Surgery (laminectomy DV10 + B/L Orchiectomy) + Pall EBRT(30Gy/10fx)+ 18 fxxzolendronate
|
Meta (5 years)
|
Ca larynx (supraglottis) Squamous cell Ca T3N2M0 - Stage IVB
|
Pall RT (30 Gy/10 fx)
|
Died at 6 months due to B/L pneumonia
|
Tobacco user (hukkah and bidi) × 35 years
|
|
71
|
Male
|
Ca Colon Adenoca T3N1M0 - Stage IIIB
|
Surgery (LAR) + Adjt CT (6×capeOx)
|
Meta (10 years)
|
Ca Prostate Adenoca, Gleason - 6 T4N1M0,PSA-16 ng/ml, Stage IV
|
EBRT (72 Gy/40 fx) + ADT (leuprorelin) × 2 years
|
Alive and disease free
|
|
|
79
|
Female
|
Ca Oral cavity (Alveolus) Squamous cell Ca T4bN2cMl - Stage IVC
|
Pall EBRT(30Gy/10fx)
|
Syn (0 months)
|
Ca esophagus Adenoca T3N1M1 - Stage IV
|
Pall EBRT (30 Gy/10 fx)
|
Died at 10 months
|
Tobacco user (khaini) × 40 years
|
|
55
|
Male
|
Ca hypopharynx (PFS) Squamous cell Ca T3N1M0 - Stage III
|
CCRT(70Gy/35fx + 4 × cisplatin)
|
Meta (9 years)
|
Ca lung Adenoca T3N1M1 - Stage IV
|
Best supportive care
|
Died at 3 months
|
Tobacco user (khaini) × 20 years
|
|
73
|
Male
|
Ca prostate Adenoca, Gleason - 7 T2N0M0, PSA-28 ng/ml - Stage IIB
|
EBRT (79 Gy/32 fx) + ADT (leuprorelin + bicalutamide)
|
Meta (1 year)
|
Ca oral cavity Squamous cell Ca T4N0M0 - Stage IVA
|
CCRT (66 Gy/33 fx + 6x carboplatin) + salvage surgery (WLE + LND)
|
Alive and disease-free
|
|
|
55
|
Male
|
Ca oral cavity (buccal mucosa) Squamous cell Ca T3N1M0 - Stage III
|
Surgery (WLE + LND) + Adjt RT(60Gy/30fx)
|
Meta (5 years)
|
Ca oropharynx (base of tongue) adenoid cystic Ca T3N0M0 - Stage III
|
Reirradiation (40 Gy/20 fx) + concurrent CT (5×carboplatin)
|
Alive with SD
|
Tobacco user (bidi and khaini) × 20 years
|
|
69
|
Female
|
Ca endometrium Endometroid Adenoca TlaNOMO- Stage IA
|
Surgery (TAH + BSO + LND)
|
Meta (6 years)
|
Ca vulva Squamous cell Ca T2N0M0 - Stage II
|
Surgery (vulvectomy + LND)
|
Alive and disease free
|
|
|
49
|
Female
|
Ca cervix Squamous cell Ca Tlb2N0M0 - Stage IIB
|
Surgery (radical hysterectomy) + Adjt EBRT (50.4 Gy/28 fx)
|
Meta (5 years)
|
Ca lung (NSCLC) Adenoca T4N3Mlb - Stage IV
|
Palliative EBRT (30 Gy/10 fx) to thorax+ Pall CT (6×PC)
|
Died at 6 months
|
|
|
30
|
Female
|
Ca breast Malignant phylloides tumor T2N0M0 - Stage IIA
|
Surgery (WLE)
|
Meta (2 years)
|
Chondrosarcoma Rt Iliac bone T2N0M0G3 - Stage III Unresectable disease
|
EBRT (60 Gy/30 fx)
|
Alive with PD
|
|
Figure 1: Age and gender distribution of study participants
The mean age at presentation of first malignancy was 54 years, while the age at presentation
of second malignancy ranged from 29 to 79 years with the average being 56 years. There
were only two patients out of the 29 patients who had a history of a first- or second-degree
relative suffering from cancer.
Ten out of the 29 (35%) patients gave a history of using tobacco in any form. Six
of these 10 patients had both such primaries that have tobacco use as a direct etiological
factor (head and neck, lung, and esophagus cancers).
Breast was the most common site of cancer in the study with nine cases (16%) closely
followed by head and neck (oral cavity, oropharynx, larynx, and hypopharynx) with
7 (12%) and lung with 6 (10%) cases, respectively [Figure 2].
Figure 2: Site-wise distribution of primary cancer sites
Carcinoma breast was also the most common first primary with seven such cases, while
among the second primaries, lung carcinoma was the most common with five patients
diagnosed with it.
All cancers were staged as per the 7th Edition of AJCC staging system (2010). Among the first primaries, five out of the
29 (17%) patients were in Stage IV at presentation, whereas among the second primaries,
16 (55%) patients were in Stage IV at presentation. Eight (28%) patients had synchronous
cancers while 21 (72%) had metachronous cancers. Among those with metachronous tumors,
the time interval between the two tumors ranged between 23 years and 1 year, with
the mean time interval being 5.33 years.
At the presentation of first primary, locoregional therapies in the form of surgery
or radiotherapy were used in 21 and 19 cases, respectively, while at the presentation
of second primary, the number of cases treated with surgery and radiotherapy reduced
to 14 and 13, respectively. Systemic therapy in the form of chemotherapy, hormonal
therapy, and targeted therapy was used in 22 and 18 patients in the treatment of first
and second primary, respectively. There were also three patients who were offered
only supportive care at presentation of second primary and one patient who refused
treatment for both first and second primary cancers [Figure 3].
Figure 3: Frequency of use of different treatment modalities in first or second primary
The intent of treatment was curative in 24 cases at presentation of first primary
and palliative in 4 (14%) cases, whereas at presentation of second primary, the intent
was curative in 16 and palliative in 12 (41%) cases. One patient refused treatment
as mentioned earlier.
Follow-up for all patients was recorded up to 1 year from the diagnosis of second
primary malignancy. Status of the patients at 1 year is displayed as a pie-chart distribution[Figure 4].
Figure 4: Status of patients at 1 year from diagnosis of second primary
The proportion of deaths in the metachronous (7 out of 21 or 33.33%) and synchronous
(3 out of 8 or 37.5%) groups were similar, and no statistical difference in survival
probability was seen (P = 0.9201) [Figure 5]. The Kaplan–Meier graph showing survival as a function of stage of the second primary
shows that all deaths occurred in Stages III and IV only [Figure 6].
Figure 5: Kaplan–Meier graph comparing survival at 1 year between metachronous (M)
and synchronous (S) groups
Figure 6: Kaplan-Meier graph comparing survival at 1 year between Stages I to IV of
the second primary cancers
Discussion
Over the past few decades, there appears to be a sharp upward trend in the occurrence
of MPMs with the prevalence ranging from 0.7% to 11.7% among various populations.[11] The possible reasons for this can be manifold including the improved survival and
life expectancy of cancer patients due to improved treatment modalities, availability
of better diagnostic technologies, and more stringent surveillance of cancer survivors.[12]
[13]
[14]
[15]
[16] In our study, 0.74% of cancer patients developed a second malignancy over a period
of 4 years. This is at the lower limit of the range and is consistent with the lower
incidence of cancer in India compared to the Western countries. Another contributing
factor may have been the fact that we have only considered solid organ malignancies
in our study and not hematological ones.
An individual with previous history of cancer has a 14% higher risk of developing
subsequent cancer than would be expected in the general population.[17] This increased incidence could be because of possible genetic susceptibility as
well as exposure to environmental carcinogens such as tobacco, alcohol, viruses, and
certain chemicals. The treatment of primary malignancy by chemotherapy and radiotherapy
may also contribute to this as both ionizing radiation and cytotoxic agents (etoposide,
cyclophosphamide, etc.,) can cause DNA damage leading to carcinogenesis. The deleterious
effects of these treatment modalities as well as of the tumor microenvironment on
the patient’s immune system may be another important contributing factor allowing
future renegade mutant cancer cells from escaping the body’s defense mechanisms. Children
and young adults may be especially prone to such iatrogenically induced cancers.[17] In our study, a total of 19 patients were treated with radiotherapy for the first
primary. Of these, only five developed cancers within the irradiated field; however,
the time interval of occurrence of these second primaries was too short (5 months
to 3 years) to be attributable to their radiation treatment. Radiation-induced solid
cancers usually have a latency period of 5–10 years or more.[18] Although the use of tamoxifen in patients of carcinoma breast, especially those
above 55 years of age, has been associated with a 2.6% increased risk of developing
endometrial carcinoma, we did not detect any second primary cancers associated with
hormone therapy use.[19]
To diagnose a second malignancy in the setting of a primary one is difficult and requires
good communication between the patient and doctor along with stringent follow-up.
Even then, the second malignancy can be masked by the symptoms of the first neoplasm
and the diagnosis confounded by possibility of local or distant recurrence of first
cancer. There are certain clinical pointers that need to be kept in mind when suspecting
a second malignancy. Fresh-onset symptoms in patients with exposure to environmental
carcinogens (e.g., smoking), suspicion of hematological malignancy after prior chemotherapy
(e.g., etoposide, anthracyclines), suspicion of secondary malignancy in patients with
prior treatment with ionizing radiation (especially if a new lesion appears in the
prior irradiated field), and any new metastatic site of disease after a prolonged
state of dormant behavior of the primary malignancy should always be investigated
to rule out a second primary cancer. Imaging of asymptomatic patients as a part of
follow-up especially with positron emission tomography (PET)–computed tomography (CT)
can be helpful in identifying new-onset lesions and give the physician lead time in
early diagnosis. However, due to high costs and repeated exposure to radiation, it
is difficult to justify its use. Hence, the need for good detailed history and clinical
examination can never be overemphasized and the possibility of a new malignancy should
always be borne in mind during follow-up of cancer patients. As listed above, use
of more stringent surveillance and screening for second cancers as well as modern
diagnostic technologies such as PET-CT, image-guided tissue biopsy, and immunohistochemistry
have also greatly contributed to increasing the diagnosis of multiple malignancies.
Certain risk factors for second primary in a patient of malignancy that have been
identified are younger age at diagnosis of primary cancer, presence of comorbidities,
lifestyle, lower stage of first cancer with a long disease-free period, phenomenon
of field cancerization, and positive family history.[11]
Although a second malignancy can be detected at any age, there is normally a predisposition
toward older age as compared to a newly diagnosed first malignancy. Several reports
have shown the mean age for reporting second cancer to be around 50 years or above.[20]
[21]
[22] In our study too, the median age at diagnosis of second malignancy was 56 years,
with 76% (22) patients above the age of 50 years. Male predominance has been reported
in many data analysis of second malignancies;[23]
[24]
[25] however, an analysis of the SEER cancer registries [6] from 1971 to 2000 showed the relative risk of developing subsequent cancers to be
higher for females than males (1.17 vs. 1.11). In our series, females were the predominant
gender with 65.5% patients with dual cancers being women. This was a direct result
of the fact that 31% (18) of cancers were almost exclusive to the female anatomy (breast,
ovary, cervix, and vulva). The high frequency of breast cancer primaries in our study
also meant that while females were more common in the age group below 60, men, whose
were mostly affected by head and neck, prostate, and lung cancers, greatly outnumbered
the women in the age group above 60 years.
The percentage of tumors in advanced stages (Stage IV) was significantly more in the
second primary tumors (55%) than the first primary tumors (17%). An explanation for
this could be the delayed diagnosis of the second primary due to its signs and symptoms
being mistaken for those of a recurrence of the first primary.
Various series of multiple malignancies have reported varying percentages of synchronous
and metachronous cancers.[9]
[10]
[26]
[27] In our study group, metachronous cancers outnumbered synchronous cancers by 2.5
times. There appeared to be no statistical difference in percentage of patients alive
or probability of survival at 1 year in the two groups. The more important factor
affecting survival at 1 year appears to be the stage of presentation of second cancer,
irrespective of whether it is synchronous or metachronous [Figure 5].
The risk of developing a second primary malignancy is varying in different cancer
sites and is known to range from 1% in hepatic cancers to up to 16% in urinary bladder
cancers.[28] Common sites of second primary malignancy after a primary cancer are respiratory,
gastrointestinal, and genitourinary malignancies.[19] According to several data analyses, the common primary malignancies seen in a multiple
cancer setting are cancers of the breast, prostate, lung, colorectal, and urinary
system.[28] In our study too, breast was the most commonly involved site of malignancy. While
lung, ovarian, and prostate were also encountered commonly, the most second common
site was of head and neck. This is in accordance with cancer statistics of our country
where tobacco-related cancers comprise about 30% of all cancers.[29] Among the 3879 patients seen at our center, those with breast cancer were the most
likely to have a second primary cancer with seven patients of dual malignancy in our
study having breast as their first primary cancer site. On the other hand, lung cancer
was the most likely second primary among all patients of our study with five patients
suffering from it as a second primary.
The most common pairs of tumors seen in our literature review were prostate–lung in
males and breast–breast or breast–colon in females.[28] Again, in our own series, the breast–colorectal remained the most common cancer
pair (3) in females while hypopharynx–lung was most common (2) in males.
Genetic susceptibility is a dominant factor in the etiology of secondary malignancies,
and patients with positive family history have an increased genetic susceptibility
to develop a second malignancy. There are several syndromes, which group the occurrence
of certain cancers together increasing the probability of one preceding the other.
Common syndromes include hereditary breast and ovary cancer syndrome (HBOC), Li Fraumeni
syndrome, Lynch syndrome, multiple endocrine neoplasia (MEN 1 and MEN 2), and von
Hippel–Lindau disease. Each of these syndromes is associated with a specific and characteristic
genetic abnormality or mutation. Prior treatment for cancer also renders the DNA susceptible
to chromosomal rearrangement or loss, leading to chromosomal abnormalities and possible
carcinogenesis.[30]
Germline and somatic mutations that play an important role in carcinogenesis are also
being recognized now as possible targets of treatment. Some of the important mutations
with respect to new treatment options and strategies are the use of poly-ADP-ribose
polymerase inhibitors in patients whose cancer displays DNA repair defects (BRCA1/2,
ATM) or checkpoint inhibitors in tumors with high mutational load as exemplified by
microsatellite instability (MSI). MSI is one genetic change that is noticed more frequently
in the setting of multiple cancers.[31] Nevertheless, commercial application of this testing to determine risk of multiple
malignancy at a high financial cost in the absence of genetic counseling cannot be
justified at the moment.[32]
[33] In our study group, only two patients had a history of cancer in their first- or
second-degree relatives. Interestingly, both of these patients had the breast–ovarian
cancer combination. While one had a history of her father suffering from lung cancer,
the other female not only developed carcinoma breast in her early twenties but she
also had an elder sister with a history of breast cancer. It is highly possible that
she could be suffering from HBOC. She was offered genetic counseling but did not undergo
testing for genetic markers for HBOC.
Continuous exposure of different mucosa to the same risk factor can lead to major
dysplastic changes, premalignant and malignant lesions. Tobacco and alcohol are the
leading causes of most aerodigestive and urogenital cancers such as head and neck,
esophagus, respiratory system, pancreas, urinary bladder, and cervix.[34]
[35]
[36] Field cancerization is a well-established phenomenon where the effect of smoking
and alcohol predisposes the entire mucosa of the aerodigestive tract or the transitional
cell mucosa of the bladder and lower urinary system to a secondary malignancy.[37] Continuing smoking and alcohol after completing treatment for the primary malignancy
increases the risk of second cancer by 35%.[17]
[38]
[39]
[40] This is a common phenomenon seen in most lower social class patients and can be
attributed to illiteracy and ignorance. In the research of continuous exposure to
a known carcinogen, smoking has emerged time and again as a high-ranking culprit.[34]
[35]
[36] Among the patients in our study, 10 had a history of using tobacco, whether smoked
or smokeless. Of these, at least six had both such malignancies that could be attributed
to tobacco. The occurrence of second primaries in these six cases can probably be
explained by field cancerization resultant from tobacco exposure. Alcohol consumption
was not recorded.
There are very little data to show survival trends in the patients of multiple malignancies.
Survival can also be affected by the advanced age of presentation and other coexisting
comorbidities. In our study, no differences in survival probability at 1 year were
seen in the metachronous or synchronous groups. Survival in a case of multiple malignancies
seems to be related to stage of presentation of each primary and is probably not a
function of the presence of multiple cancers itself.
The possible fallacies of our study are that it is retrospective in nature with a
sample size not big enough for robust statistical analysis.
Conclusion
While the incidence of multiple primary cancers appears to be increasing, early diagnosis
of a second primary in the background of an existing malignancy remains a challenge.
Screening for second malignancies is an attractive option, but the optimal screening
modalities with cost-effectiveness in mind elude us for most cancers.[41] With regular monitoring, accompanied by careful history taking, thorough examination,
and appropriate investigations, second primary tumors could be detected earlier and
with timely intervention might be better managed with improvement in survival. Patient
counseling about lifestyle modifications, especially smoking and alcohol cessation,
are even more important in cancer survivors than in those without a history of the
disease.
Our data can possibly sensitize practicing oncologists toward the prevalence of the
dual malignancies and other MPMs in the Indian population and help develop an index
of suspicion for their early detection.
