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Forty-nine-month survival in a metastatic renal cell carcinoma patient across six lines of targeted therapy. A better understanding of the aetiopathogenetic molecular targets in renal cell carcinoma (RCC) and the subsequent advent of targeted therapeutic agents have greatly improved the management and prognosis of RCC and patient survival. Renal cell carcinoma (RCC) has been one of the most widely studied cancers in recent years; however, despite a considerable improvement in our understanding of RCC tumour biology, the unpredictable and aggressive natural history of RCC and the associated complexities in its management often pose important clinical dilemmas. A 45-year-old male presented to our centre in October 2008 for medical management of mRCC; his personal and family history was insignificant, and he had no major co-morbidities. A routine follow-up PET-CT within two months of initiation of therapy with everolimus and Bevacizumab showed a considerable reduction in the size and metabolic activity of the LRF mass, prevascular, right hilar, and retrocrural lymph nodal, pulmonary, and skeletal metastases, indicating a favourable response to therapy with a significant clinical benefit (Figure 3). Recently conducted routine follow-up investigations, including a pulmonologist review, were insignificant, except mild pericardial effusion anterior to the right atrium on echocardiography. Although surgery remains the mainstay of RCC treatment, metastatic disease warrants medical management [6].
Although targeted agents have demonstrable anti-tumour activity and prolonged PFS in mRCC, patients often develop resistance to first-line VEGFR-TKI therapy within 6–11 months of therapy and eventually experience disease progression [10]. Clinical practice guidelines in the United States and Europe uniformly recommend everolimus as the standard of care in mRCC that has failed first-line VEGFR-TKI therapy, based on robust clinical evidence from the 410-patient RECORD-1 study [11].
In the case of mRCC progression beyond second-line therapy, currently, there exists no level 1 evidence for any targeted agent, although dovitinib is being studied in a phase III trial in this setting [12]. Although renal cancer is largely resistant to chemotherapy, with response rates of 5–15%, some chemotherapeutic agents, such as 5-fluorouracil, have been shown to have some activity in RCC [13]. Combination therapy is alternatively being evaluated in mRCC, with the goal of achieving additive or synergistic anti-tumour effects, including enhanced tumour shrinkage or a more durable response; however, concerns regarding cumulative toxicities of these agents due to target profile overlaps remain [15]. The biological hypothesis surrounding a synergistic effect of inhibiting both VEGF and mTOR signalling with specifically targeted agents is compelling [17]. The advent of several targeted agents and ongoing research on many more are anticipated to significantly improve the prognosis of mRCC. This patient represents a case of effective medical management of clinically aggressive, metastatic RCC through the application of sequential and combination therapy with VEGF- and mTOR-directed agents over six lines, resulting in a survival of more than 48 months. When a piece of pet equipment has been enhanced to a certain degree, it can be upgraded to the next level, increasing the chance of getting better stats from refining. In MP dungeons, all participants can see pet info and their positions in the team formation, but only the team leader can adjust pet positions.
However, optimising therapeutic outcomes through appropriate sequential or combination therapy remains a challenge. Almost one third of RCC patients present with metastatic disease, and half of those who undergo surgery eventually develop distant metastasis [1–3].
In May 2008, he had been diagnosed with advanced RCC (left kidney) that had metastasised to the lungs along with tumour thrombi in the left renal vein. Subsequently, the patient remained disease free for five months, and a follow-up PET-CT in October 2009 revealed local recurrence of the tumour in the left renal fossa (LRF) along with mediastinal, retroperitoneal, bilateral hilar and left supraclavicular nodal and bilateral lung metastases, indicating disease progression.

PET-CT in August 2011 (b) shows ~35–40% increase in the size of the LRF mass and appearance of multiple vertebral lesions compared to PET-CT in February 2011 (a), indicating disease progression.
PET-CT in November 2011 (b) shows ~50–100% increase in the size of the pulmonary lesions, ~15% increase in the size of the LRF mass, and appearance of new pleural deposits compared to PET-CT in August 2011 (a), indicating disease progression. Thus far, the patient has completed seven cycles of treatment with this combination, and the eighth cycle is in progress. The patient appears to be tolerating the drugs well, with occasional stomatitis, diarrohea, and fatigue as therapy-related adverse events (TRAEs), and continues concurrent radiotherapy along with adequate nutritional supplementation and supportive care.
The erstwhile relative dearth of treatment options for mRCC has been transformed into an embarrassment of the riches [5], owing to our much improved understanding of the various aetiopathogenetic signal transduction pathways and targets in mRCC.
PET-CT after initiation of therapy with everolimus and bevacizumab (b) shows a considerable reduction in the size and metabolic activity of the LRF mass, prevascular, right hilar, and retrocrural lymph nodal, pulmonary, and skeletal metastases compared to PET-CT before therapy. Preclinical data suggest some mechanisms for the development of VEGFR-TKI resistance, including reemergence of tumour vasculature or upregulation of alternate tumour survival and invasiveness pathways.
However, in clinical practice, reintroduction of a VEGFR-TKI following disease progression on a VEGFR-TKI and an mTOR inhibitor is increasingly being applied, based on sparsely available data [4].
Therefore, chemotherapy is generally used in combination with other therapies or can be a therapeutic option for patients who have failed to respond to targeted therapy. Although the rationale for combined inhibition of critical pathways remains strong, attempts at combining the currently available targeted agents have been discouraging. However, in the future, the clinician’s priority would be the optimal identification and application of these agents to balance clinical benefit with the quality of life of the patient. Appropriate sequential monotherapy and combination therapy with agents that have non-overlapping target profiles minimised treatment-related toxicities, thereby enabling our patient to tolerate therapy at full doses. He underwent a left radical nephrectomy with regional lymphadenectomy in the same month, and surgical histopathology revealed grade II clear cell RCC. Consequently, both sequential monotherapy and combination therapy with targeted agents are being explored, since they can potentially diminish the impact of tumour angiogenic escape mechanisms and prolong disease control.
There are, however, previous and current, retrospective and prospective, studies on the clinical application of a second VEGFR-TKI (such as axitinib) in first-line VEGFR-TKI failure, based on its relative potency and target selectivity [10].
VEGFR-TKI rechallenge may be associated with a sub-optimal clinical benefit owing to partial cross-resistance.
Clinical evidence of a fourth line of therapy in mRCC was recently reported in a 52-year-old male patient, treated sequentially with sunitinib, everolimus, sorafenib, and temsirolimus, leading to a PFS of 48 months; therapy with each agent was well tolerated, and there was no apparent cumulative toxicity, suggesting that patients could continue to derive clinical benefit from multiple lines of therapy [14]. A phase III CALGB trial is currently investigating second-line use of everolimus alone versus a combination of everolimus and bevacizumab [16]. Ongoing studies on sequential and combination therapy with targeted agents in mRCC are expected to provide insights into the most optimal management approaches and further enhance survival. Survival and prognosis of mRCC patients can thus be significantly improved with suitable use of newer targeted therapeutic agents. Appropriate therapy with agents that have non-overlapping target profiles minimised treatment-related toxicities, enabling our patient to tolerate therapy at full doses.

Studies aiming to determine the optimal use of these agents, including the most effective sequence of therapy and the relative efficacy of combination versus sequential single-agent therapy, are ongoing; however, presently, physician preferences, drug toxicity profiles, patient compliance, and therapy costs usually dictate the choice of targeted therapy. The ECOG status improved from 2 to 1 with the first four lines of therapy; however, the ECOG status increased to 2 with increased vertebral and pulmonary lesions. However, a therapy with these targeted agents is rarely curative, and therapeutic resistance is common; therefore, patients often have to rely on multiple lines of therapy for a sustained clinical benefit [8]. Sequential administration of VEGFR-TKIs may result in cumulative class-effect toxicities, such as hypertension, hand–foot syndrome, and rash, owing to overlaps between their target selectivity. Our patient was also advised a VEGFR-TKI (sorafenib) after disease progression on everolimus; however, he experienced subsequent disease progression on therapy.
Resistance to both mTOR- and VEGF-directed therapies appears to be at least partially transient; thus resensitisation might be an option in patients who exhibit good tolerability to treatment, allowing sustained disease control through multiple iterations of therapy. Both these agents are relatively specific inhibitors and, in contrast to other combinations of targeted agents, can be administered concurrently at full doses [18]. This case represents a good example of a significant clinical benefit of targeted therapy beyond the fourth line in mRCC. Here, we describe a case of mRCC with lung metastasis at presentation that was treated effectively for four years with six lines of targeted agents sequentially and in combination. Then, an early post-treatment follow-up PET-CT conducted in May 2010 showed an increase in the size and metabolic activity of the soft tissue thickening in the LRF and a 10–15% increase in the number, size, and metabolic activity of the retroperitoneal, mediastinal, bilateral hilar and left supraclavicular lymph nodal and bilateral lung metastases, indicating progressive disease. Many ongoing studies are hence focused on determining the most optimal sequence of these targeted therapeutic agents and the relative efficacy of sequential monotherapy versus combination therapy.
Since the toxicity profiles of mTOR inhibitors and VEGFR-TKIs do not overlap, the use of a second-line mTOR inhibitor following first-line VEGFR-TKI failure minimises the chances of VEGFR-TKI-associated class-effect toxicities. Therapeutic agents that are capable of inhibition of multiple angiogenic pathways over a wide spectrum, in addition to VEGF signalling, are therefore being evaluated in the third line. The survival and prognosis of mRCC patients may thus be significantly improved with the suitable use of newer targeted agents.
However, definitive guidance on the relative efficacy of a second VEGFR-TKI versus an mTOR inhibitor in first-line VEGFR-TKI failure appears to be lacking and can be derived only from large, randomised head-to-head comparisons of these agents. Since these studies involved a combination of two VEGF-targeted agents, the amplification of treatment-related toxicities offset the observed enhancement in tumour response to therapy. Until such data become available, the choice of second-line therapy after first-line VEGFR-TKI failure would be determined by careful consideration of factors such as the distinct safety profiles of targeted agents, patient history, and co-morbidities.

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