A 39-year-old female, in her 31st week of pregnancy, presented with a 5 cm breast nodule with inflammatory signs. From ultrasound, it was suspected to be invasive cancer; subsequent biopsy confirmed a diagnosis of invasive adeno-carcinoma. From 14 October 2015 to 18 February 2016, she received neo-adjuvant chemotherapy with four cycles of 90 mg/sqm epirubicin and 600 mg/sqm cyclophosphamide by i.v. infusion, with each cycle occurring every four weeks, followed by weekly 80 mg/sqm paclitaxel by i.v. infusion. This treatment was interrupted on 18 February 2016 because of disease progression. On 3 March 2016, she underwent a radical left mastectomy; post-operative histology showed infiltrating ductal carcinoma without lympho-vascular invasion. pT2 No Mo was the post-operative TNM classification, G3, ER+ (30%) Pr+ (10%), Ki67 90%, and HER2 negative. From 28 April 2016 to 04 July 2016, she received adjuvant chemotherapy with three cycles of CMF (600/40/600 mg/sqm on days 1, 8, and 28, by i.v. infusion) and, from 31 May 2016 to 08 July 2016, she received conventional radiotherapy on the chest wall and lymph-nodes at II–III–IV levels. From 29 July 2016 to 1 February 2017, 25 mg of exemestane daily plus an LHRH agonist every 28 days were administered. On 2 February 2017, exemestane was replaced by tamoxifen because a hormonal assessment showed the recovery of ovarian functionality. On 22 May 2017, diffusion whole body magnetic resonance imaging (MRI) was carried out at the European Institute of Oncology, in Milan, and it signaled an 8 mm nodule of the middle lung lobe, which was suspected for relapse. A 13 mm nodule in the same site of the suspected relapse was confirmed on 30 May 2017 by WB CT. The subsequent biopsy showed that the nodule had malignant characteristics. On 13 June 2017, the metastatic lung nodule was removed by atypical lung resection. The immunophenotype from post-operative histology confirmed that the primary breast cancer was the probable origin; ER, PR, and Ki67 were 30%, negative, and 50%, respectively. From 18 July 2017 to 24 August 2017, the patient received four cycles of liposomal doxorubicin. From 18 September 2017 to date, this patient received four consecutive cycles of IT twice, and the last cycle was followed by one month of rest and then four successive cycles of oral ChT with vinorelbine and capecitabine. In contrast to previous reports on the metronomic use of vinorelbine and capecitabine [,,] in breast cancer patients with detectable metastatic disease, one week of ChT interruption was planned because our patient did not show clinical-radiological evidence of metastatic disease. Vinorelbine at 30 mg was given every other day, and 500 mg of capecitabine was given three times a day continuously, on days 1–14 every 21 days. On 8 October 2018 and 16 October 2019, bone scanning (BS) and WB CT, respectively, were negative for relapse and circulating CEA-TPA-CA.15.3 levels were in the normal range on 14 October 2019.\nA study [] evaluated 103 breast cancer patients who underwent surgery for suspected pulmonary metastases. In this study, the median survival time (ST) was 29 months and the three-year survival was 43% in 14 patients with a disease-free interval (DFI) of less than 24 months. All patients had received complete resections of their lung metastases. Another study [] reported that, in 37 recruited breast cancer patients with completely resected pulmonary metastases (27 with a single pulmonary nodule (SPN) and 10 with two or more pulmonary nodules), the actuarial five-year survival was 59%. However, in five of them with a DFI of one year or less, the mean survival was only 15 ± 3.6 months, and all patients were dead at 26 months. Before, after, or both before and after thoracotomy, all 37 patients received ChT, tamoxifen, or both. Similarly, in another series [] of 40 patients (most of them with one or two pulmonary metastases) who had undergone complete pulmonary resection, the five-year survival rate was 35.6%, while the median DFI following complete pulmonary resection was 1.6 years. Most breast oncologists, even in SPN cases, prefer systemic medical treatment to surgery. In fact, pulmonary metastasis is considered a systemic disease, and poor survival rates have been reported for those with a DFI of <3 years or with discordance in the hormone receptor status between the primary cancer and the SPN [,].
On 16 August 2011, a 64-year-old male physician with no relevant co-morbidity was suspected for transversal colon cancer by colonoscopy. On 26 August 2011, seven likely secondary lesions were detected by abdominal ultrasound in different hepatic segments (the biggest lesion was 42 mm in the largest diameter) and 15 ng/mL was the serum CEA level. On 29 August 2011, he underwent hemicolectomy of the transversal colon, and adeno-carcinoma, G2/G4 was found in post-operative histology. pT3 N2a (6 regional lymph-nodes involved of 22 examined) M1 was the post-operative TNM classification. Kras was wild type. From 14 October 2011 to 20 July 2012, he received 1000 sqm/day capecitabine given orally and 130 mg/sqm oxaliplatin by i.v. infusion (the Xelox regimen) on days 1–14 every 21 days (one cycle) for six cycles, plus 5 mg/kg bevacizumab by i.v. infusion every two weeks followed by maintenance therapy with capecitabine and bevacizumab. His serum CEA level, which was 52 ng/mL at the beginning of chemotherapy, decreased to 25 ng/mL in July 2012, and the WB CT showed slight decreases in all hepatic metastases. On 11 September 2012, all detectable liver metastases were surgically removed following his demand and, in October 2012, his serum CEA level was in the normal range. In December 2012, a radiological assessment documented a suspected secondary lung nodule in addition to the recovery of metastatic liver disease; the serum CEA value was 5.9 ng/mL, which increased to 66 ng/mL in January 2013. From January to April 2013, he received seven cycles of 130 mg/sqm irinotecan by i.v. infusion and 500 mg/sqm cetuximab by i.v. infusion every two weeks. On 2 July 2013, he underwent surgical removal of the left liver lobe; contemporaneously, other secondary lesions were enucleated (overall, ten liver metastases were removed); post-operative histology confirmed the secondary origin of the liver lesions, while a subsequent abdominal MRI signaled three regions with necrotic features. WB positron emission tomography (PET) was negative for residual metastatic liver disease. On 28 February 2013 and 1 July 2013, the serum CEA level was in the normal range. On 21 August 2013, thoracic CT showed an increase in the previously detected nodule placed at the inferior left lung lobe, while liver ultra-sonography showed two small hypo-echogenic areas suspected to be surgical scars. On 29 August 2013, the patient underwent atypical resection of the inferior left lung lobe and post-operative histology confirmed that it was a secondary lesion compatible with primary colorectal cancer. The serum CEA level was 9 ng/mL at the end of September/beginning of October. On 24 October 2013, WB CT signaled a new focal liver lesion that was 57 mm in the largest diameter and a 16 mm nodule at the lower-basal region of the right lung: both were suspected for relapse. Following oncologic consultation, from November 2013 to January 2014, he received cycles with FOLFIRI plus cetuximab. In January 2014, the serum CEA level was in the normal range. In March 2014, he underwent surgical removal of the liver nodule and of the other two nodules in the right lung (one of them was a pleural lesion); they were all determined to be secondary lesions in the post-operative histology. He continued to receive the same FOLFIRI treatment for a total of six cycles until June 2014. In July 2014, WB CT showed multiple new bilateral lung nodules. On 19 September 2014, he accepted the invitation to be included in an experimental clinical trial that was recruiting previously treated patients who had progressed under cetuximab after an initial benefit. He was selected because of his high MET level, as assessed in a biologic sample; therefore, he was given 120 mg of tivantinib (a MET-inhibitor) orally twice daily and cetuximab until 25 October 2016, with an initial clinical-radiological partial response (PR) followed by a stable disease as documented by WB PET carried out on 27 May 2016. In addition, WB PET showed a likely metastatic lesion of the lateral eighth right rib; therefore, from 13 June 2016 to 17 June 2016, in addition to tivantinib and cetuximab, he underwent RT at the rib lesion (25 Gy as a total dose by five fractionated doses). During treatment with tivantinib plus cetuximab, the serum CEA value, which was measured every 2–3 months, was in the normal range until 21 September 2016, when it was found to be 12 ng/mL. On 04 November 2016, WB PET documented the progression of the secondary lesion of the eighth right rib. On 2 December 2016, the patient underwent palliative surgical removal of the lateral arch of the VIII rib; post-operative histology confirmed the metastatic origin of the rib lesion with infiltration of the surgical edges. On 27 December 2016, surgical intervention for soft rib tissue radicalization and the removal of the middle lobe of the right lung was carried out; post-operative histology confirmed the metastatic origin of the residual disease. On 15 February 2017, WB CT showed multiple bilateral suspected secondary pulmonary lesions; the biggest was 7 mm in the largest diameter in the right lung. On 15 February 2017, he was given regorafenib, which he interrupted on 23 May 2017 because of strong side effects and the rising serum CEA level. On 17 August 2017, WB CT documented the progression of the disease at the level of the previously treated eighth rib lesion and the appearance of two new suspected lung lesions on the thoracic wall and lower right lobe (29 × 13 mm), respectively. The remaining multiple bilateral pulmonary lesions, the biggest of which was 8 mm in the largest diameter, were substantially stable. On 15 September 2017, WB PET signaled at least four suspected lung lesions and pathological activity of the VII, VIII, and IX right ribs. On 21 September 2017 and 20 November 2017, serum CEA values were 11.2 and 96 ng/mL, respectively. In November 2017, he again started treatment with the Xelox regimen plus cetuximab. After two cycles, oxaliplatin was interrupted because of strong side effects and he continued with capecitabine and cetuximab. On 13 February 2018, the serum CEA value was 46.3 ng/mL. In March 2018, WB PET confirmed the progression of metastatic disease in the right lung and right chest wall; on 20 March 2018, following transient ChT interruption, the patient underwent surgical removal of the lower right pulmonary lobe, multiple resections of the residual left lung, and thoracotomy of the VII, VIII, and IX right ribs with subsequent plastic surgery of the thoracic wall. The control with WB CT, which was carried out soon after surgery, showed that one metastatic lesion remained on the right lobe, in addition to the multiple repetitions of the left lung lobe. He started with capecitabine and cetuximab therapy, which he continued until March 2019. Serum CEA values, which were 4.1, 4.5, 3.6, 4, and 5.1 ng/mL on 6 April 2018, 24 May 2018, 1 August 2018, 10 October 2018, and 27 October 2018, respectively, increased to 12 ng/mL in December 2018. WB CT carried out in January 2019 signaled three new hepatic repetitions, the largest of which was about 2 cm, and two of them were close to the hepatic and cava veins, respectively, while the multiple lung repetitions were stable. At the beginning of April 2019, he underwent surgical removal of the hepatic lesions. Yet another WB CT carried out soon after surgery showed the persistence of metastatic liver disease in addition to the stable multiple lung repetitions. At the beginning of July 2019, he entered an experimental protocol with temozolomide that was interrupted at the end of August after two cycles because of the unresponsive metastatic disease. On 16 August, the serum CEA value was 86 ng/mL. On 2 September, following an oncologic consultation, he was given tas-102 therapy, which is ongoing. Although this patient is not disease-free, he is doing well with 0-1 ECOG PS 98 months after primary surgery.\nThis patient underwent an uncommon number of surgical interventions (nine) and, during a prolonged time of post-operative monitoring, serum CEA was often in the normal range. Therefore, in this patient, surgery, in addition to a systemic treatment, likely allowed for the maintenance of an undetectable or detectable, but relatively low metastatic tumor burden. Five-year OS rates of 30%–43% were reported in patients who were submitted to complete pulmonary metastasectomy following hepatic resection for colorectal metastases at an earlier stage []. Similarly, a 30% five-year OS rate and a median OS ranging from 29 to 40.5 months was reported in a study [] in which 206 inoperable patients with pulmonary oligo-metastases were treated with stereotactic body radiotherapy (SBRT). In 118 (57%) of these 206 patients, colorectal carcinoma was the primary site of pulmonary oligo-metastases. Moreover, Marudanayagam et al. [] reported a 53% five-year OS after combined liver and lung resections for patients in which the pulmonary metastases developed more than six months after liver resection (metachronous group). However, 0% was the four-year OS for those in which, as in our patient, lung metastasis developed within six months after liver resection (synchronous group).