Review Case Report For reprint orders, please contact: [email protected]
2014
Long-term survival in small cell lung cancer: a case report and review of the literature Alfredo Tartarone*,1, Rosa Lerose2, Raffaele Ardito1, Laura Troiani1, Beatrice Tedesco1, Giovanni Bozza1, Rodolfo Cangiano1 & Michele Aieta1
3
8
2 1 7 /
uture
all cell eview of
ture , UK
Abstract: Small cell lung cancer (SCLC) represents approximately 13% of all newly diagnosed lung cancers. SCLC is a very aggressive disease characterized by early locoregional and distant metastases. The median survival is 14–16 months for patients with limited disease and 8–11 months for those with extensive disease, with 20–40% of patients with limited disease and 5% of patients with extensive disease alive at 2 years. This report discusses the case of a long-term SCLC survivor treated with radiotherapy, several lines of chemotherapy and long-acting somatostatin analogues who is alive 7 years after diagnosis, with no evidence of further relapse. In the near future, better identification of prognostic and predictive factors based on models that integrate clinical data and multiple gene expression profiles and the use of novel treatments could increase the number of long-term SCLC survivors. Small cell lung cancer (SCLC) represents approximately 15% of all newly diagnosed lung cancers, and is strongly associated with tobacco smoking. SCLC is a very aggressive disease characterized by early locoregional and distant metastases. The median survival is 14–16 months for patients with limited disease (LD) and 8–11 months for those with extensive disease (ED), with 20–40% of patients with LD and 5% of patients with ED alive at 2 years [1] . Thus, there is an imperative need for a novel therapeutic approach for this type of lung cancer. For this reason, many novel and targeted agents, including the combination of chemotherapy and gene therapy, are under evaluation in SCLC [2] . Here, we report the case of a long-term survivor SCLC patient treated with radiotherapy, several lines of chemotherapy and long-acting somatostatin analogs.
Keywords
• cancer survivor • chemotherapy • long‑acting somatostatine analogs • octreotide scan • small cell lung cancer • somatostatin receptors
Case report In January 2006, a 67-year-old man, a heavy smoker, received a diagnosis of LD-SCLC with expression of somatostatin receptors shown by an 111-In octreotide scan (Octreoscan™; Mallinckrodt Medical BV, The Netherlands) (Figure 1) . He was first treated with combination chemotherapy of cisplatin 80 mg/m 2 on day 1 and etoposide 100 mg/m 2 on days 1–3 (PE regimen) repeated every 3 weeks for six cycles, followed by thoracic irradiation (total dose administered 60 Gy) and prophylactic cranial irradiation (PCI). A subsequent CT scan did not show any residual disease. At the same time, the patient began treatment with the long-acting somatostatin analog octreotide 30 mg subcutaneously every 28 days, which is still ongoing. From February to July 2007 owing to thoracic progressive disease (time to progression [TTP]: 13 months) the patient, in agreement with local hospital guidelines, received six cycles of second-line chemotherapy with topotecan 1.5 mg/m2 days 1–5 every 28 days, Division of Medical Oncology, Centro di Riferimento Oncologico di Basilicata, I.R.C.C.S., via Padre Pio 1, 85028 Rionero in Vulture (PZ), Italy 2 Hospital Pharmacy, Centro di Riferimento Oncologico di Basilicata, I.R.C.C.S., Rionero in Vulture (PZ), Italy *Author for correspondence: Tel: +39 0972726111; Fax: +39 0972723509; [email protected] 1
10.2217/FON.13.213 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(4), 523–528
part of
ISSN 1479-6694
523
Case Report Tartarone, Lerose, Ardito et al.
Figure 1. Octreoscan™ (Mallinckrodt Medical BV, The Netherlands) shows an accumulation of radiotracer in the upper lobe of the right lung.
achieving a partial response. From December 2008 to March 2009, owing to local progressive disease (TTP: 17 months), a rechallenge with PE for five cycles was administered obtaining a stable disease. From April to August 2009 owing to a new thoracic progression of disease (TTP: 1 month), also characterized by the appearance of lesions in the left lung, six cycles of docetaxel 75 mg/m2 on day 1 every 3 weeks were administered (Figure 2) . A CT scan made after the third and the sixth cycle of chemotherapy showed stable disease. An Octreoscan, performed after the last cycle of docetaxel, confirmed a tracer uptake increase in the upper lobe of the right lung (Figure 3) . Treatment with the long-acting somatostatin analog octreotide has been well tolerated with no severe hematological and nonhematological toxicities. The use of octreotide, in view of the result of the Octreoscan, the good tolerability and in the absence of therapeutic alternatives was continued beyond progression and after the suspension of chemotherapy, although this does not represent a standard approach. However, during maintenance therapy with octreotide, CT scans showed the disappearance of the lesions in the left lung and stability of parenchymal consolidation of the right upper lobe (Figure 4) . Tumoral markers (neuron-specific enolase and chromogranin A) were always within normal limits. To date, 7 years after diagnosis the patient is alive with a good performance status and with no evidence of further relapse.
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Discussion SCLC is characterized by rapid growth and early onset of distant metastases. The differential diagnosis of SCLC includes either typical or atypical pulmonary carcinoid, rare neuroendocrine lung tumors. Atypical carcinoid tumors are usually situated at the lung periphery, unlike SCLC. Immunohistochemically, cytokeratins may show a similar dot-like staining pattern; chromogranin A reactivity is greater in carcinoid tumor, whereas TTF-1 staining and, particularly, Ki-67 labeling index are more prominent in SCLC [3] . In our case, a careful analysis of hematoxylin and eosin sections with evaluation of tumor cell proliferation by Ki-67 labeling index confirmed the diagnosis of SCLC (Figure 5) . Management of LD-SCLC typically includes combination platinum-based chemotherapy and concurrent thoracic radiotherapy [4] . Thoracic radiotherapy increases local control and survival in LD patients. A meta-analysis of 13 randomized trials showed that thoracic radiotherapy increases 3-year survival from 8.9 to 14.3% [5] . Patients who experience a complete response to initial therapy should be offered PCI. Auperin et al. performed a meta-analysis of randomized trials of PCI in LD-SCLC and showed a 5% overall survival advantage in patients who received PCI [6] . Patients with ED-SCLC are treated with combination chemotherapy. Most evidence supports the recommendation of platinum/etoposide as the standard of care [1] . A study performed by the Japanese Cooperative Oncology Group reported an encouraging survival benefit in favor of irinotecan/cisplatin compared with etoposide/cisplatin [7] . However, two subsequent confirmative studies failed to reproduce the Japanese data [8,9] . Patients with relapsed SCLC have an extremely poor prognosis. In particular, patients whose disease relapses within 6 months of completion of therapy have few chances of responding to additional chemotherapy. At present, there are limited options for treatment of SCLC in the second-line setting. Patients may also respond to a rechallenge with platinum-based therapy, but the duration of response is typically diminished. Topotecan and cyclophosphamide, doxorubicin and vincristine (CAV) were evaluated in a randomized study of patients with SCLC who relapsed after first-line therapy [10] . In this study, topotecan was as effective as CAV and resulted in improved control of several symptoms. Topotecan received US FDA approval for recurrent SCLC in its intravenous and oral form.
future science group
Long-term survival in small cell lung cancer: a case report & review of the literature In our case, second-line chemotherapy with topotecan achieved a partial response while a stable disease was obtained with subsequent lines of chemotherapy, including a rechallenge with the PE regimen. Somatostatin (SRIF) is a regulatory-inhibitory peptide with exocrine, endocrine, paracrine and autocrine activity [11] . High levels of SRIF expression are generally detected in neuroendocrine tumors, including SCLC. The biological effects of SRIF are mediated through a family of 5 G-protein coupled receptors (SSTR1–5). As reported by Susini et al., there exists a number of direct and indirect mechanisms by which somatostatin analogs can exert antitumor effects [12] . The direct antiproliferative actions of somatostatin analogs may be the result of blocking cell division or result from the induction of apoptosis following interaction with the somatostatin receptor. The indirect antiproliferative somatostatin effect on tumor growth may derive both from the suppression of the synthesis of growth factors and by an antiangiogenic activity through the inhibition of VEGF, PDGF and FGF [11,12] . Synthetic derivatives of somatostatin have similar activity to native somatostatin, but with a longer half-life. The long-acting somatostatin analogs octreotide and lanreotide are usually employed for the treatment of acromegaly and gastroenteropancreatic endocrine tumors. Studies reported in the literature have shown little or no effect of somatostatin analogs in the treatment of SCLC [11–16] . Some data suggest that the direct antiproliferative effect of somatostatin analogs may enhance chemotherapy activity. In a recent Greek study, 130 SCLC patients with positive somatostatin receptors were treated with only chemotherapy (paclitaxel plus carboplatin) or chemotherapy plus lanreotide; median time to progression and median survival were statistically better in the experimental arm [11] . In our case, the use of octreotide, decided in light of the persistent positive result of the Octreoscan and the good tolerability, was continued beyond progression and after the suspension of chemotherapy as maintenance therapy, although this does not represent a standard approach; however, surprisingly during maintenance therapy with octreotide, radiological examinations showed a significant regression of thoracic disease. The treatment of SCLC remains a challenge; in fact, despite initial efficacy of combination chemotherapy and radiotherapy the response
future science group
Case Report
Figure 2. CT scan demonstrates areas of pathological consolidation in the lower lobe of the left lung.
is usually short lived and the prognosis has not changed over the past few decades. To improve this outcome, several therapeutic approaches have been tested, including maintenance treatment. To assess the role of maintenance or consolidation therapy in the treatment of SCLC, Rossi et al. published a meta-analysis of 21 published randomized clinical trials, encompassing 3668 patients [17] . The authors concluded that the maintenance or the consolidation approach failed to improve the outcomes of SCLC. Several signaling pathways have been found to be activated in SCLC, forming a rationale for targeted therapies. Many novel and targeted agents including antiangiogenic agents, tyrosine kinase inhibitors, c-MET inhibitors and IGF-1 inhibitors are under evaluation in SCLC; a combination of chemotherapy and gene therapy (chemogene therapy) is another promising practice for these patients [2,18] .
Figure 3. Recent CT scan demonstrates no signs of recurrent disease.
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Case Report Tartarone, Lerose, Ardito et al.
Figure 4. Octreoscan™ (Mallinckrodt Medical BV, The Netherlands) performed at the end of chemotherapy confirmed a tracer uptake increase in the upper lobe of the right lung.
p53 represents one of the earliest mutations seen during lung carcinogenesis, and approximately 20% of SCLCs have inactivating mutations of the p53 gene. Preliminary experiences of p53 gene replacement therapy have demonstrated the feasibility of the procedure in a number of cancers including lung cancer [19] . Recently, for the first time two research groups have sequenced and analyzed the genomes of SCLC, identifying new gene mutations that could drive the development of new therapies [20,21] . Preliminary results of a comprehensive mutation analysis program conducted at Memorial Sloan–Kettering Cancer Center in patients with SCLC were reported at the last American Society of Clinical Oncology meeting [22] . The authors showed that a molecular evaluation of SCLC is
Figure 5. Histological specimen of the small cell lung cancer patient (hematoxylin and eosin staining): small tumor cells are densely packed, with scant cytoplasm, finely granular nuclear chromatin and absence of nucleoli.
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feasible using the small biopsy specimens usually available in clinical practice [22] . Models that integrate clinical data and multiple gene expression profiles could represent a new tool to better classify SCLC and predict prognosis and response to treatment. With respect to prognostic factors, Hermes et al. in a retrospective analysis of 397 SCLC patients reported that stage of disease, performance status and LDH serum levels are independent prognostic factors for survival [23] . Recently, the presence of circulating tumor cells has been demonstrated in the blood of patients with various solid tumors including SCLC [24] . Several studies have demonstrated that circulating tumor cells may play a significant role in determining the prognosis of SCLC patients and may help the physician to treat patients with a favorable prognosis with more intensive therapy [25,26] . Few data are available in the literature about long-term SCLC survivors. A French multicenter study included 263 SCLC patients from 52 institutions who survived longer than 30 months. This study demonstrated that relapsing 30-month survivors can benefit from second-line treatment with 5- and 10-year survival rates of 68 and 44%, respectively, and that 13% of patients developed a second primary cancer [27] . Lassen et al. selected 60 5-year SCLC survivors from 1714 patients who entered in clinical trials between 1973 and 1991 [28] . The conclusion of this study is that long-term survival can be achieved in both stages of SCLC and that secondary primary cancers occur more frequently than late relapses, representing the main cause of death in these patients. The authors of two previous studies recommend a monitoring for development of a second primary cancer for patients who achieve long-term survival. Finally, a Polish study analyzed 111 SCLC patients who survived for more than 2 years after diagnosis. The authors concluded that the minimum time of survival predicting a significant reduced risk of recurrence of SCLC is 3 years and that the chance of long-term survival strongly correlates with LD [29] . Conclusion Our case is a rare example of a SCLC patient surviving long term despite recurrence of disease. The patient was successfully treated with radiotherapy, chemotherapy and also by treatment with somatostatin analogs. Previous reported experiences have shown that in the context of a disease with a very poor prognosis, there exists a small group of
future science group
Long-term survival in small cell lung cancer: a case report & review of the literature patients with a surprisingly long survival. In the near future, a better identification of prognostic and predictive factors based on models that integrate clinical data and multiple gene expression profiles and the use of novel treatments could increase the number of long-term SCLC survivors. Future perspective To date, progress in the therapy of SCLC has been particularly slow. The way forward will involve a better understanding of the biology of the disease in order to develop more effective therapies. In addition, models that integrate clinical data and multiple gene expression profiles are needed to better classify SCLC and predict prognosis and response to treatment.
Case Report
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Informed consent disclosure The authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.
Executive summary ●●
Scanty therapeutic advances have been made in recent years in the treatment of small cell lung cancer.
●●
However, in the context of a disease with a very poor prognosis there exists a small group of patients with a surprisingly long survival time.
●●
We reported a case of a long-term survivor of small cell lung cancer treated with radiotherapy, several lines of chemotherapy and long-acting somatostatin analogs.
References
6
Papers of special note have been highlighted as: • of interest •• of considerable interest 1
Puglisi M, Dolly S, Faria A et al. Treatment options for small cell lung cancer: do we have more choice? Br. J. Cancer 102, 629–638 (2010).
2
Joshi M, Ayoola A, Belani CP. Small-cell lung cancer: an update on targeted therapies. Adv. Exp. Med. Biol. 779, 385–404 (2013).
3
Pelosi G, Rodriguez J, Viale G et al. Typical and atipica pulmonary carcinoid tumor overdiagnosed as small cell carcinoma on biopsy specimens. Am. J. Surg. Pathol. 29, 179–187 (2005).
•
4
5
Reports on how to perform a differential diagnosis between small cell lung cancer (SCLC) and either typical or atypical pulmonary carcinoid. Sorensen M, Pijls-Johannesma M, Felip E. Small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 21(Suppl. 5), v120–v125 (2010). Pignon JP, Arriagada R, Ihde DC et al. A meta-analysis of thoracic radiotherapy for small cell lung cancer. N. Engl. J. Med. 327, 1618–1624 (1992).
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7
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Auperin A, Arriagada R, Pignon JP et al. Prophylactic cranial irradiation for patients with small cell lung cancer in complete remission. N. Engl. J. Med. 341, 476–484 (1999). Noda K, Nishiwaki Y, Kawahara M et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin in patients with previously untreated extensive small cell lung cancer. N. Engl. J. Med. 346, 85–91 (2002). Hanna N, Bunn PA, Langer C et al. Randomized Phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small cell lung cancer. J. Clin. Oncol. 24, 2038–2043 (2006). Lara PN, Natale R, Crowley J et al. Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J. Clin. Oncol. 27, 2530–2535 (2009).
10 Von Pawel J, Schiller JH, Shepherd FA et al.
Topotecan versus cyclophosphamide, doxorubicin and vincristine for the treatment of recurrent small cell lung cancer. J. Clin. Oncol. 17, 658–667 (1999). 11 Zarogoulidis K, Eleftheriadou E, Kontakiotis
T et al. Long acting somatostatin analogues in combination to antineoplastic agents in the
treatment of small cell lung cancer patients. Lung Cancer 76, 84–88 (2012). •• Combination of long-acting somatostatin analogs and chemotherapy show efficacy in SCLC patients. 12 Susini C, Buscail L. Rationale for the use of
somatostatin analogs as antitumor agents. Ann. Oncol. 17, 1733–1742 (2006). •
Comprehensive paper about the use of somatostatin analogs in cancer patients.
13 Macaulay VM, Smith IE, Everard MJ et al.
Experimental and clinical studies with somatostatin analogue octreotide in small cell lung cancer. Br. J. Cancer 64, 451–456 (1991). 14 Cotto C, Quoix E, Thomas F et al. Phase I
study of the somatostatin analogue somatuline in refractory small cell lung cancer. Ann. Oncol. 5, 290–291 (1994). 15 Marschke RF, Grill JP, Sloan JA et al. Phase II
study of high-dose somatostatin analogue in patients either previously treated or untreated who have extensive-stage small cell lung cancer. Am. J. Clin. Oncol. 22, 15–17 (1999). 16 Hejna M, Schmidinger M, Raderer M. The
clinical role of somatostatin analogues as antineoplastic agents: much ado about nothing? Ann. Oncol. 13, 653–668 (2002). 17 Rossi A, Garassino MC, Cinquini M et al.
Maintenance or consolidation therapy in
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suppression by adenoviral PTEN gene therapy combined with cisplatin chemotherapy in small cell lung cancer. Cancer Gene Ther 20(4), 251–259 (2013). 19 Roth JA. Gene therapy in thoracic
oncology. Ann. Thorac. Surg. 85, 1837–1838 (2008). 20 Rudin CM, Durinck S, Stawiski EW et al.
Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small cell lung cancer. Nat. Genet. 44, 1111–1116 (2012). •• A research group has sequenced and analyzed the genomes of SCLC, identifying new gene mutations that could drive the development of new therapies.
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21 Peifer M, Fernandez-Cuesta L, Sos ML et al.
Integrative genome analyses identify key somatic driver mutations of small cell lung cancer. Nat. Genet. 44, 1104–1110 (2012).
26 Hiltermann TJ, Pore MM, van den Berg A
et al. Circulating tumor cells in small-cell lung cancer: a predictive and prognostic factor. Ann. Oncol. 23, 2337–2342 (2012).
•• Identifies key driver mutations of SCLC. 22 Pietanza MC, Varghese AM, Won HH et al.
Prospective molecular evaluation of small cell lung cancer (SCLC) utilizing the comprehensive mutation analysis program at Memorial Sloan-Kettering Cancer Center (MSKCC). J. Clin. Oncol. 31(Suppl.), Abstract 7600 (2013). 23 Hermes A, Waschki B, Gatzemeier U et al.
Characteristics, treatment patterns and outcomes of patients with small cell lung cancer: a retrospective single institution analysis. Lung Cancer 71, 363–366 (2011). 24 Allard WJ, Matera J, Miller MC et al. Tumor
cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin. Cancer Res. 10, 6897–6904 (2004).
•
Role of circulating tumor cells as a prognostic factor in SCLC.
27 Jacoulet P, Depierre A, Moro A et al.
Long-term survivors of small-cell lung cancer (SCLC): a French multi center study. Ann. Oncol. 8, 1009–1014 (1997). 28 Lassen U, Osterlind K, Hansen M et al. Long-
term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years. An analysis of 1714 consecutive patients. J. Clin. Oncol. 13, 1215–1220 (1995). 29 Lewinski T, Zulawski M. Small cell lung
cancer survival: 3 years as a minimum for predicting a favorable outcome. Lung Cancer 40, 203–213 (2003).
25 Naito T, Tanaka F, Ono A et al. Prognostic
impact of circulating tumor cells in patients
Future Oncol. (2014) 10(4)
future science group
2014
Long-term survival in small cell lung cancer: a case report and review of the literature Alfredo Tartarone*,1, Rosa Lerose2, Raffaele Ardito1, Laura Troiani1, Beatrice Tedesco1, Giovanni Bozza1, Rodolfo Cangiano1 & Michele Aieta1
3
8
2 1 7 /
uture
all cell eview of
ture , UK
Abstract: Small cell lung cancer (SCLC) represents approximately 13% of all newly diagnosed lung cancers. SCLC is a very aggressive disease characterized by early locoregional and distant metastases. The median survival is 14–16 months for patients with limited disease and 8–11 months for those with extensive disease, with 20–40% of patients with limited disease and 5% of patients with extensive disease alive at 2 years. This report discusses the case of a long-term SCLC survivor treated with radiotherapy, several lines of chemotherapy and long-acting somatostatin analogues who is alive 7 years after diagnosis, with no evidence of further relapse. In the near future, better identification of prognostic and predictive factors based on models that integrate clinical data and multiple gene expression profiles and the use of novel treatments could increase the number of long-term SCLC survivors. Small cell lung cancer (SCLC) represents approximately 15% of all newly diagnosed lung cancers, and is strongly associated with tobacco smoking. SCLC is a very aggressive disease characterized by early locoregional and distant metastases. The median survival is 14–16 months for patients with limited disease (LD) and 8–11 months for those with extensive disease (ED), with 20–40% of patients with LD and 5% of patients with ED alive at 2 years [1] . Thus, there is an imperative need for a novel therapeutic approach for this type of lung cancer. For this reason, many novel and targeted agents, including the combination of chemotherapy and gene therapy, are under evaluation in SCLC [2] . Here, we report the case of a long-term survivor SCLC patient treated with radiotherapy, several lines of chemotherapy and long-acting somatostatin analogs.
Keywords
• cancer survivor • chemotherapy • long‑acting somatostatine analogs • octreotide scan • small cell lung cancer • somatostatin receptors
Case report In January 2006, a 67-year-old man, a heavy smoker, received a diagnosis of LD-SCLC with expression of somatostatin receptors shown by an 111-In octreotide scan (Octreoscan™; Mallinckrodt Medical BV, The Netherlands) (Figure 1) . He was first treated with combination chemotherapy of cisplatin 80 mg/m 2 on day 1 and etoposide 100 mg/m 2 on days 1–3 (PE regimen) repeated every 3 weeks for six cycles, followed by thoracic irradiation (total dose administered 60 Gy) and prophylactic cranial irradiation (PCI). A subsequent CT scan did not show any residual disease. At the same time, the patient began treatment with the long-acting somatostatin analog octreotide 30 mg subcutaneously every 28 days, which is still ongoing. From February to July 2007 owing to thoracic progressive disease (time to progression [TTP]: 13 months) the patient, in agreement with local hospital guidelines, received six cycles of second-line chemotherapy with topotecan 1.5 mg/m2 days 1–5 every 28 days, Division of Medical Oncology, Centro di Riferimento Oncologico di Basilicata, I.R.C.C.S., via Padre Pio 1, 85028 Rionero in Vulture (PZ), Italy 2 Hospital Pharmacy, Centro di Riferimento Oncologico di Basilicata, I.R.C.C.S., Rionero in Vulture (PZ), Italy *Author for correspondence: Tel: +39 0972726111; Fax: +39 0972723509; [email protected] 1
10.2217/FON.13.213 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(4), 523–528
part of
ISSN 1479-6694
523
Case Report Tartarone, Lerose, Ardito et al.
Figure 1. Octreoscan™ (Mallinckrodt Medical BV, The Netherlands) shows an accumulation of radiotracer in the upper lobe of the right lung.
achieving a partial response. From December 2008 to March 2009, owing to local progressive disease (TTP: 17 months), a rechallenge with PE for five cycles was administered obtaining a stable disease. From April to August 2009 owing to a new thoracic progression of disease (TTP: 1 month), also characterized by the appearance of lesions in the left lung, six cycles of docetaxel 75 mg/m2 on day 1 every 3 weeks were administered (Figure 2) . A CT scan made after the third and the sixth cycle of chemotherapy showed stable disease. An Octreoscan, performed after the last cycle of docetaxel, confirmed a tracer uptake increase in the upper lobe of the right lung (Figure 3) . Treatment with the long-acting somatostatin analog octreotide has been well tolerated with no severe hematological and nonhematological toxicities. The use of octreotide, in view of the result of the Octreoscan, the good tolerability and in the absence of therapeutic alternatives was continued beyond progression and after the suspension of chemotherapy, although this does not represent a standard approach. However, during maintenance therapy with octreotide, CT scans showed the disappearance of the lesions in the left lung and stability of parenchymal consolidation of the right upper lobe (Figure 4) . Tumoral markers (neuron-specific enolase and chromogranin A) were always within normal limits. To date, 7 years after diagnosis the patient is alive with a good performance status and with no evidence of further relapse.
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Future Oncol. (2014) 10(4)
Discussion SCLC is characterized by rapid growth and early onset of distant metastases. The differential diagnosis of SCLC includes either typical or atypical pulmonary carcinoid, rare neuroendocrine lung tumors. Atypical carcinoid tumors are usually situated at the lung periphery, unlike SCLC. Immunohistochemically, cytokeratins may show a similar dot-like staining pattern; chromogranin A reactivity is greater in carcinoid tumor, whereas TTF-1 staining and, particularly, Ki-67 labeling index are more prominent in SCLC [3] . In our case, a careful analysis of hematoxylin and eosin sections with evaluation of tumor cell proliferation by Ki-67 labeling index confirmed the diagnosis of SCLC (Figure 5) . Management of LD-SCLC typically includes combination platinum-based chemotherapy and concurrent thoracic radiotherapy [4] . Thoracic radiotherapy increases local control and survival in LD patients. A meta-analysis of 13 randomized trials showed that thoracic radiotherapy increases 3-year survival from 8.9 to 14.3% [5] . Patients who experience a complete response to initial therapy should be offered PCI. Auperin et al. performed a meta-analysis of randomized trials of PCI in LD-SCLC and showed a 5% overall survival advantage in patients who received PCI [6] . Patients with ED-SCLC are treated with combination chemotherapy. Most evidence supports the recommendation of platinum/etoposide as the standard of care [1] . A study performed by the Japanese Cooperative Oncology Group reported an encouraging survival benefit in favor of irinotecan/cisplatin compared with etoposide/cisplatin [7] . However, two subsequent confirmative studies failed to reproduce the Japanese data [8,9] . Patients with relapsed SCLC have an extremely poor prognosis. In particular, patients whose disease relapses within 6 months of completion of therapy have few chances of responding to additional chemotherapy. At present, there are limited options for treatment of SCLC in the second-line setting. Patients may also respond to a rechallenge with platinum-based therapy, but the duration of response is typically diminished. Topotecan and cyclophosphamide, doxorubicin and vincristine (CAV) were evaluated in a randomized study of patients with SCLC who relapsed after first-line therapy [10] . In this study, topotecan was as effective as CAV and resulted in improved control of several symptoms. Topotecan received US FDA approval for recurrent SCLC in its intravenous and oral form.
future science group
Long-term survival in small cell lung cancer: a case report & review of the literature In our case, second-line chemotherapy with topotecan achieved a partial response while a stable disease was obtained with subsequent lines of chemotherapy, including a rechallenge with the PE regimen. Somatostatin (SRIF) is a regulatory-inhibitory peptide with exocrine, endocrine, paracrine and autocrine activity [11] . High levels of SRIF expression are generally detected in neuroendocrine tumors, including SCLC. The biological effects of SRIF are mediated through a family of 5 G-protein coupled receptors (SSTR1–5). As reported by Susini et al., there exists a number of direct and indirect mechanisms by which somatostatin analogs can exert antitumor effects [12] . The direct antiproliferative actions of somatostatin analogs may be the result of blocking cell division or result from the induction of apoptosis following interaction with the somatostatin receptor. The indirect antiproliferative somatostatin effect on tumor growth may derive both from the suppression of the synthesis of growth factors and by an antiangiogenic activity through the inhibition of VEGF, PDGF and FGF [11,12] . Synthetic derivatives of somatostatin have similar activity to native somatostatin, but with a longer half-life. The long-acting somatostatin analogs octreotide and lanreotide are usually employed for the treatment of acromegaly and gastroenteropancreatic endocrine tumors. Studies reported in the literature have shown little or no effect of somatostatin analogs in the treatment of SCLC [11–16] . Some data suggest that the direct antiproliferative effect of somatostatin analogs may enhance chemotherapy activity. In a recent Greek study, 130 SCLC patients with positive somatostatin receptors were treated with only chemotherapy (paclitaxel plus carboplatin) or chemotherapy plus lanreotide; median time to progression and median survival were statistically better in the experimental arm [11] . In our case, the use of octreotide, decided in light of the persistent positive result of the Octreoscan and the good tolerability, was continued beyond progression and after the suspension of chemotherapy as maintenance therapy, although this does not represent a standard approach; however, surprisingly during maintenance therapy with octreotide, radiological examinations showed a significant regression of thoracic disease. The treatment of SCLC remains a challenge; in fact, despite initial efficacy of combination chemotherapy and radiotherapy the response
future science group
Case Report
Figure 2. CT scan demonstrates areas of pathological consolidation in the lower lobe of the left lung.
is usually short lived and the prognosis has not changed over the past few decades. To improve this outcome, several therapeutic approaches have been tested, including maintenance treatment. To assess the role of maintenance or consolidation therapy in the treatment of SCLC, Rossi et al. published a meta-analysis of 21 published randomized clinical trials, encompassing 3668 patients [17] . The authors concluded that the maintenance or the consolidation approach failed to improve the outcomes of SCLC. Several signaling pathways have been found to be activated in SCLC, forming a rationale for targeted therapies. Many novel and targeted agents including antiangiogenic agents, tyrosine kinase inhibitors, c-MET inhibitors and IGF-1 inhibitors are under evaluation in SCLC; a combination of chemotherapy and gene therapy (chemogene therapy) is another promising practice for these patients [2,18] .
Figure 3. Recent CT scan demonstrates no signs of recurrent disease.
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525
Case Report Tartarone, Lerose, Ardito et al.
Figure 4. Octreoscan™ (Mallinckrodt Medical BV, The Netherlands) performed at the end of chemotherapy confirmed a tracer uptake increase in the upper lobe of the right lung.
p53 represents one of the earliest mutations seen during lung carcinogenesis, and approximately 20% of SCLCs have inactivating mutations of the p53 gene. Preliminary experiences of p53 gene replacement therapy have demonstrated the feasibility of the procedure in a number of cancers including lung cancer [19] . Recently, for the first time two research groups have sequenced and analyzed the genomes of SCLC, identifying new gene mutations that could drive the development of new therapies [20,21] . Preliminary results of a comprehensive mutation analysis program conducted at Memorial Sloan–Kettering Cancer Center in patients with SCLC were reported at the last American Society of Clinical Oncology meeting [22] . The authors showed that a molecular evaluation of SCLC is
Figure 5. Histological specimen of the small cell lung cancer patient (hematoxylin and eosin staining): small tumor cells are densely packed, with scant cytoplasm, finely granular nuclear chromatin and absence of nucleoli.
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feasible using the small biopsy specimens usually available in clinical practice [22] . Models that integrate clinical data and multiple gene expression profiles could represent a new tool to better classify SCLC and predict prognosis and response to treatment. With respect to prognostic factors, Hermes et al. in a retrospective analysis of 397 SCLC patients reported that stage of disease, performance status and LDH serum levels are independent prognostic factors for survival [23] . Recently, the presence of circulating tumor cells has been demonstrated in the blood of patients with various solid tumors including SCLC [24] . Several studies have demonstrated that circulating tumor cells may play a significant role in determining the prognosis of SCLC patients and may help the physician to treat patients with a favorable prognosis with more intensive therapy [25,26] . Few data are available in the literature about long-term SCLC survivors. A French multicenter study included 263 SCLC patients from 52 institutions who survived longer than 30 months. This study demonstrated that relapsing 30-month survivors can benefit from second-line treatment with 5- and 10-year survival rates of 68 and 44%, respectively, and that 13% of patients developed a second primary cancer [27] . Lassen et al. selected 60 5-year SCLC survivors from 1714 patients who entered in clinical trials between 1973 and 1991 [28] . The conclusion of this study is that long-term survival can be achieved in both stages of SCLC and that secondary primary cancers occur more frequently than late relapses, representing the main cause of death in these patients. The authors of two previous studies recommend a monitoring for development of a second primary cancer for patients who achieve long-term survival. Finally, a Polish study analyzed 111 SCLC patients who survived for more than 2 years after diagnosis. The authors concluded that the minimum time of survival predicting a significant reduced risk of recurrence of SCLC is 3 years and that the chance of long-term survival strongly correlates with LD [29] . Conclusion Our case is a rare example of a SCLC patient surviving long term despite recurrence of disease. The patient was successfully treated with radiotherapy, chemotherapy and also by treatment with somatostatin analogs. Previous reported experiences have shown that in the context of a disease with a very poor prognosis, there exists a small group of
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Long-term survival in small cell lung cancer: a case report & review of the literature patients with a surprisingly long survival. In the near future, a better identification of prognostic and predictive factors based on models that integrate clinical data and multiple gene expression profiles and the use of novel treatments could increase the number of long-term SCLC survivors. Future perspective To date, progress in the therapy of SCLC has been particularly slow. The way forward will involve a better understanding of the biology of the disease in order to develop more effective therapies. In addition, models that integrate clinical data and multiple gene expression profiles are needed to better classify SCLC and predict prognosis and response to treatment.
Case Report
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Informed consent disclosure The authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.
Executive summary ●●
Scanty therapeutic advances have been made in recent years in the treatment of small cell lung cancer.
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However, in the context of a disease with a very poor prognosis there exists a small group of patients with a surprisingly long survival time.
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We reported a case of a long-term survivor of small cell lung cancer treated with radiotherapy, several lines of chemotherapy and long-acting somatostatin analogs.
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