{"product_id":"new-and-established-treatments-for-aggressive-pituitary-tumors-and-pituitary-carcinomas-a-guide-for-patients","title":"New and Established Treatments for Aggressive Pituitary Tumors and Pituitary Carcinomas: A Guide for Patients","description":"\u003cp\u003eThis review summarizes current and emerging treatments for aggressive pituitary tumors and pituitary carcinomas, based on the revised European Society of Endocrinology clinical practice guideline. Temozolomide remains the first-line therapy, producing complete or partial tumor shrinkage in about 40% of patients and stable disease in one third, but one third of patients progress on it. Emerging options include molecular-guided targeted drugs, immune-checkpoint inhibitors, bevacizumab, and peptide receptor radionuclide therapy (PRRT). Immune-checkpoint inhibitors produced a response in about half of 38 reported cases. Each option has specific response rates and open questions about the best timing and patient selection.\u003c\/p\u003e\n\n\u003ch1\u003eNew and Established Treatments for Aggressive Pituitary Tumors and Pituitary Carcinomas: A Guide for Patients\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#diagnosis\"\u003eHow Aggressive Pituitary Tumors and Pituitary Carcinomas Are Defined\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#markers\"\u003eMarkers That May Predict Aggressive Behavior\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#conventional\"\u003eEstablished Treatment Options: Conventional Therapies\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#temozolomide\"\u003eTemozolomide: The First-Line Treatment\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#loco-regional\"\u003eLoco-Regional Therapies for Limited Spread\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#molecular\"\u003eEmerging Option 1: Molecular-Guided Druggable Targets\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#immunotherapy\"\u003eEmerging Option 2: Immunotherapy (Immune-Checkpoint Inhibitors)\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#bevacizumab\"\u003eEmerging Option 3: Bevacizumab\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#prrt\"\u003eEmerging Option 4: Peptide Receptor Radionuclide Therapy (PRRT)\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#implications\"\u003eClinical Implications: What This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations: What This Review Could Not Prove\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations and Practical Advice\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eTemozolomide remains first-line after standard therapy fails: about 40% of patients respond with tumor shrinkage, one third have stable disease, and one third progress.\u003c\/li\u003e\n\u003cli\u003eImmune-checkpoint inhibitors showed benefit in about half of 38 reported cases, with pituitary carcinomas responding better than aggressive pituitary tumors.\u003c\/li\u003e\n\u003cli\u003eBevacizumab monotherapy produced stable disease in most of 14 patients; no clinical trial or large cohort exists for bevacizumab.\u003c\/li\u003e\n\u003cli\u003ePRRT worked better in 11 patients not previously given temozolomide than in 20 who had received it; no clinical trial or large cohort exists for PRRT.\u003c\/li\u003e\n\u003cli\u003eMolecular testing on recent tumor tissue is recommended after progression on temozolomide to guide emerging treatment choices.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This Research Matters\u003c\/h2\u003e\n\u003cp\u003eManaging aggressive pituitary tumors and pituitary carcinomas remains a difficult challenge for doctors and patients alike. This review article examines the treatments that are currently available. The review also looks at treatments that are still emerging.\u003c\/p\u003e\n\n\u003cp\u003eThe authors organized the review around the recently published Revised European Society of Endocrinology Clinical Practice Guideline for the management of aggressive pituitary tumors and pituitary carcinomas. The review covers established treatment options, with a focus on temozolomide. It also covers emerging treatment options, with a focus on four areas:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eMolecular-guided druggable targets (treatments aimed at specific gene changes in the tumor)\u003c\/li\u003e\n  \u003cli\u003eImmune-checkpoint inhibitors (drugs that help the immune system attack the tumor)\u003c\/li\u003e\n  \u003cli\u003eBevacizumab (a drug that blocks blood vessel growth in tumors)\u003c\/li\u003e\n  \u003cli\u003ePeptide receptor radionuclide therapy, or PRRT (a treatment that delivers radiation directly to tumor cells)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eFor each treatment option, the authors discuss how well the tumor responds, which factors predict a response to treatment, what side effects occur, and what questions remain for the future.\u003c\/p\u003e\n\n\u003ch2 id=\"diagnosis\"\u003eHow Aggressive Pituitary Tumors and Pituitary Carcinomas Are Defined\u003c\/h2\u003e\n\u003cp\u003eAccording to the revised European Society of Endocrinology clinical practice guideline, the diagnosis of an aggressive pituitary tumor should be considered in patients with a radiologically-invasive tumor. A radiologically-invasive tumor is one that imaging scans show has grown into surrounding structures. In addition, the patient must have either an unusually rapid tumor growth rate or clinically relevant tumor growth despite optimal standard therapy.\u003c\/p\u003e\n\n\u003cp\u003eAn aggressive pituitary tumor is also called an aggressive pituitary neuroendocrine tumor, or PitNET. Standard therapies include surgery, radiotherapy, and conventional medical treatments. The conventional medical treatments are somatostatin receptor ligands and dopamine type 2 receptor agonists.\u003c\/p\u003e\n\n\u003cp\u003ePituitary carcinomas are also named metastatic PitNETs. These tumors are very rare. Doctors can diagnose a pituitary carcinoma only when the tumor has spread to the brain or spine (craniospinal metastases) or to other parts of the body (systemic metastases). From a practical perspective, defining pituitary carcinomas by the presence of metastasis makes the extension work-up critical. The extension work-up is important not only for guiding the treatment strategy, but also for establishing the diagnosis in the first place.\u003c\/p\u003e\n\n\u003cp\u003eImportantly, metastases may be detected at any time. The time from the initial diagnosis to the detection of metastases can range from several months to many years.\u003c\/p\u003e\n\n\u003ch2 id=\"markers\"\u003eMarkers That May Predict Aggressive Behavior\u003c\/h2\u003e\n\u003cp\u003ePredicting future aggressive behavior remains challenging. Researchers have speculated that so-called 2B* tumors might be suspected of malignancy. A 2B* tumor is defined as an invasive and highly proliferative tumor, with a Ki67 index of 10% or higher. The Ki67 index is a laboratory measure of how fast tumor cells are dividing.\u003c\/p\u003e\n\n\u003cp\u003eAlong the same lines, researchers have also proposed that an initial Ki67 index of 10% or higher might be an early marker of aggressiveness. Other markers associated with aggressive pituitary tumors and carcinomas include specific gene changes, called somatic pathogenic variants:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eATRX and TP53 pathogenic variants are encountered especially in corticotroph tumors (tumors that produce the hormone ACTH).\u003c\/li\u003e\n  \u003cli\u003eSF3B1 and TP53 pathogenic variants are found in lactotroph tumors (tumors that produce prolactin).\u003c\/li\u003e\n  \u003cli\u003eAneuploidy, which is an abnormal number of chromosomes caused by widespread chromosomal loss of heterozygosity, has also been reported in corticotroph carcinomas and aggressive pituitary tumors.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"conventional\"\u003eEstablished Treatment Options: Conventional Therapies\u003c\/h2\u003e\n\u003cp\u003eThe revised guidelines recommend several therapies for aggressive pituitary tumors and carcinomas. First, the guidelines recommend repeat surgery performed by an expert neurosurgeon. Second, the guidelines recommend radiotherapy, which may include adjuvant radiotherapy and\/or a second course of radiotherapy. Third, the guidelines recommend maximally tolerated doses of conventional pituitary-directed medical treatments. These medical treatments include somatostatin receptor ligands for somatotroph, corticotroph and thyrotroph tumors, and cabergoline for lactotroph and somatotroph tumors.\u003c\/p\u003e\n\n\u003cp\u003eOf note, the guidelines suggest considering early adjuvant radiotherapy even before aggressive behavior is proved. Doctors should consider this approach for patients with residual tumor in the presence of pathological or molecular markers associated with aggressiveness. Specifically, the guidelines include three groups here:\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003eGrade 2B* tumors\u003c\/li\u003e\n  \u003cli\u003eLactotroph tumors that are resistant to dopamine type 2 receptor agonists and that carry SF3B1 or TP53 pathogenic variants\u003c\/li\u003e\n  \u003cli\u003eMacrocorticotroph tumors that carry ATRX or TP53 pathogenic variants\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003ch2 id=\"temozolomide\"\u003eTemozolomide: The First-Line Treatment\u003c\/h2\u003e\n\u003cp\u003eBoth the initial and the revised guidelines recommend temozolomide as the first-line treatment for aggressive pituitary tumors and carcinomas. Temozolomide is an oral alkylating therapy, which means it is a pill that damages the DNA of tumor cells. Doctors use temozolomide after standard therapy has failed and after tumor progression has been documented.\u003c\/p\u003e\n\n\u003cp\u003eThe revised guidelines recommend temozolomide monotherapy for 12 months in patients who respond to the drug. A longer duration of treatment could be considered to obtain a maximal response in the absence of side effects. In patients who do not respond, and who show tumor progression after three cycles, temozolomide treatment should be stopped.\u003c\/p\u003e\n\n\u003cp\u003eThe Stupp protocol is another option. The Stupp protocol combines temozolomide with radiotherapy, followed by temozolomide alone. This protocol appears to have a higher response rate in aggressive pituitary tumors and carcinomas, although data remain limited. Doctors could consider the Stupp protocol in rare cases of rapid tumor progression of a large residual tumor that is inaccessible to additional surgery. Doctors could also consider the Stupp protocol when pathological or molecular markers suggest a poor prognosis, or when a rapid tumor response is required.\u003c\/p\u003e\n\n\u003cp\u003eTemozolomide remains first-line therapy because it has reasonable effectiveness. Around 40% of patients show complete or partial radiological response, and one third of patients show stable disease. However, one third of patients progress on first-line temozolomide. Even if the initial response is encouraging, an important proportion of tumors may recur or progress again after temozolomide is stopped. Moreover, a second trial of temozolomide is less effective.\u003c\/p\u003e\n\n\u003cp\u003eNevertheless, the revised guidelines suggest a second trial of temozolomide in patients with recurrence following a prior complete or partial response to the first course of temozolomide.\u003c\/p\u003e\n\n\u003ch3\u003ePredictors of Response to Temozolomide\u003c\/h3\u003e\n\u003cp\u003eSo far, the only potential predictor of response to temozolomide in aggressive pituitary tumors and carcinomas appears to be the methylguanine methyltransferase (MGMT) status. MGMT is a protein that repairs DNA damage. However, results on MGMT status have been inconsistent. It is no longer recommended to perform MGMT immunohistochemistry before a trial of temozolomide.\u003c\/p\u003e\n\n\u003cp\u003eRegarding the histological type and secretory status, the first European Society of Endocrinology survey concluded that functioning tumors responded better to temozolomide. That survey found no further difference among histological types of functioning tumors. Similarly, a meta-analysis identified better response to temozolomide in functioning tumors compared with non-functioning tumors.\u003c\/p\u003e\n\n\u003ch3\u003eSide Effects of Temozolomide\u003c\/h3\u003e\n\u003cp\u003eTemozolomide is associated with both acute and late toxicities. The revised guidelines note that treatment duration with temozolomide exceeding 24 months must be weighed against the potential risk for cumulative severe toxicity. This risk includes secondary malignancies, which are new cancers caused by the treatment.\u003c\/p\u003e\n\n\u003cp\u003eIn addition, both in gliomas and in aggressive pituitary tumors and carcinomas, use of temozolomide is associated, at least in some patients, with temozolomide-induced hypermutation. Hypermutation means the drug causes many new mutations in the tumor's DNA. Temozolomide-induced hypermutation may make immune-checkpoint inhibitors more effective. At the same time, it raises the question of whether alternative treatments should be considered for aggressive pituitary tumors before using temozolomide.\u003c\/p\u003e\n\n\u003cp\u003eImportantly, in low-grade gliomas, temozolomide-induced hypermutation was demonstrated to be associated with high-grade histology at recurrence. It was also associated with both an increased risk of distant recurrence and reduced survival after high-grade transformation. Whether these associations apply also to aggressive pituitary tumors and carcinomas has not been investigated yet.\u003c\/p\u003e\n\n\u003cp\u003eThus, perspectives regarding temozolomide include improving its effectiveness. One way is to combine temozolomide with radiotherapy or other drugs. Another way is to identify predictors of response to temozolomide. A further perspective is potentially reconsidering the role of temozolomide as the primary therapy for aggressive pituitary tumors and carcinomas.\u003c\/p\u003e\n\n\u003ch2 id=\"loco-regional\"\u003eLoco-Regional Therapies for Limited Spread\u003c\/h2\u003e\n\u003cp\u003eIf oligo-metastatic disease is present, the revised guidelines suggest loco-regional therapies. Oligo-metastatic disease means the cancer has spread to only a few sites. Loco-regional therapies include surgery, radiotherapy, radiofrequency or microwave ablation, chemoembolization, or bland embolization. Doctors may use these therapies either alone or combined with systemic treatment.\u003c\/p\u003e\n\n\u003ch2 id=\"molecular\"\u003eEmerging Option 1: Molecular-Guided Druggable Targets\u003c\/h2\u003e\n\u003cp\u003eAfter temozolomide failure, the initial guidelines suggested a trial with other systemic cytotoxic therapy. However, the authors of the initial guidelines were unable to suggest a particular regimen at that time. This was because of the variety of chemotherapeutic agents that had been reported and the lack of evidence. Since then, more data have accumulated. These data led to significant changes in the revised guidelines.\u003c\/p\u003e\n\n\u003cp\u003eFirst, to guide potential treatment choices, the revised guidelines suggest molecular testing in patients with tumor progression on temozolomide. This molecular testing may provide information on specific gene alterations that can be targeted therapeutically. It may also provide additional information, such as the tumor mutational burden and the mismatch repair deficiency status.\u003c\/p\u003e\n\n\u003cp\u003eRegarding the utility of molecular profiling in aggressive pituitary tumors and carcinomas, a recent study by Paes and colleagues sequenced a cohort of 20 patients with prolactinomas. The study aimed to identify somatic genetic alterations. By doing so, they identified a somatic activating mutation in the estrogen receptor alpha gene in a patient with an aggressive lactotroph tumor resistant to temozolomide. This finding led to treatment with elacestrant, a second-line estrogen-receptor degrader.\u003c\/p\u003e\n\n\u003cp\u003eElacestrant was initiated after the third course of radiotherapy was completed. The treatment managed to significantly reduce prolactin levels and to control tumor growth for the available follow-up.\u003c\/p\u003e\n\n\u003cp\u003eAnother important point is that the respective somatic mutation was present on the tissue sample from the fourth surgery. However, the same mutation was absent on the tissue samples from the first and second surgeries. This finding underlines the need for a recent tissue sample for molecular profiling.\u003c\/p\u003e\n\n\u003cp\u003eIn addition, Lin and colleagues demonstrated that different lesions from the same patient may harbor different molecular profiles. These different profiles may influence the response to treatment, and more specifically the response to immune-checkpoint inhibitors in the respective study.\u003c\/p\u003e\n\n\u003cp\u003eIn line with this, the revised guidelines note that performing genomic analysis on recent tumor tissue is important. The guidelines therefore suggest considering minimal invasive surgical biopsy, as it poses minimal risk. Having tissue available from different tumor sites in the case of pituitary carcinomas appears equally important.\u003c\/p\u003e\n\n\u003ch2 id=\"immunotherapy\"\u003eEmerging Option 2: Immunotherapy (Immune-Checkpoint Inhibitors)\u003c\/h2\u003e\n\u003cp\u003eAmong emerging treatment options, immune-checkpoint inhibitors (ICIs) have gained the most attention in recent years. The revised guidelines suggest considering a trial with ICIs in patients with pituitary carcinoma and rapid tumor progression after treatment with temozolomide. The guidelines also note that tumor-agnostic data support the use of ICIs in tumors that are either mismatch repair deficient or exhibit high tumor mutational burden. This supports the use of ICIs in pituitary tumors with these molecular features.\u003c\/p\u003e\n\n\u003cp\u003eICIs work by blocking immune checkpoints, which are the \"brakes\" of the immune system. By blocking these brakes, ICIs reactivate and enhance anti-tumoral immune responses. More specifically, the ICIs used so far for the treatment of pituitary tumors block cytotoxic T-lymphocyte-associated protein (CTLA4) in the case of ipilimumab. The ICIs block programmed cell death protein 1 (PD-1) in the case of nivolumab and pembrolizumab.\u003c\/p\u003e\n\n\u003cp\u003eThese molecules were used either as combined therapy (nivolumab plus ipilimumab) or as monotherapy. The monotherapy was usually pembrolizumab, but nivolumab monotherapy was also used.\u003c\/p\u003e\n\n\u003ch3\u003eHow Well Do Immune-Checkpoint Inhibitors Work?\u003c\/h3\u003e\n\u003cp\u003eThe tumor response of 38 pituitary cases has so far been reported. These cases come from several sources:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eA cohort of 15 cases\u003c\/li\u003e\n  \u003cli\u003eA phase 2 clinical trial of nine cases\u003c\/li\u003e\n  \u003cli\u003eAnother phase 2 clinical trial of four cases\u003c\/li\u003e\n  \u003cli\u003eCases from the second European Society of Endocrinology survey\u003c\/li\u003e\n  \u003cli\u003eIsolated case reports\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eAll 38 patients received multimodal treatment before ICI start. This multimodal treatment included temozolomide in at least 36 cases.\u003c\/p\u003e\n\n\u003cp\u003eUnder ICIs, the tumor responses were as follows:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eComplete response in one case (2.6%)\u003c\/li\u003e\n  \u003cli\u003ePartial response in nine cases (23.6%)\u003c\/li\u003e\n  \u003cli\u003eStable disease in nine cases (23.6%)\u003c\/li\u003e\n  \u003cli\u003eProgression in 19 cases (half of the tumors)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eHowever, as with all treatments, one should bear in mind that different studies or case reports have evaluated the tumor response differently. The duration of the response is also variable.\u003c\/p\u003e\n\n\u003ch3\u003ePredictors of Response to Immune-Checkpoint Inhibitors\u003c\/h3\u003e\n\u003cp\u003eRegarding predictors of response to treatment, the authors' cohort study identified that tumor type was a major predictor of response to ICIs. Pituitary carcinomas responded better than aggressive pituitary tumors. With the publication of more data, this difference persists, although it appears to become less pronounced.\u003c\/p\u003e\n\n\u003cp\u003eAs noted in the revised guidelines, mismatch repair deficiency and high tumor mutational burden are known predictors in other cancers. Tumor mutational burden appears promising as a predictive factor of response in aggressive pituitary tumors and carcinomas as well. However, it is noteworthy that a high tumor mutational burden has been associated with a favorable radiological response in most, but not all, treated cases. Similarly, although mismatch repair deficiency appears promising, not all mismatch repair-deficient cases responded to ICIs.\u003c\/p\u003e\n\n\u003cp\u003eRegarding the histological type, the treated cases consist of 24 corticotroph tumors, 12 lactotroph tumors, one Pit1 silent tumor and one somatotroph tumor. The responses among corticotroph tumors were:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eOne corticotroph tumor showed complete response\u003c\/li\u003e\n  \u003cli\u003eSix (25%) showed partial response\u003c\/li\u003e\n  \u003cli\u003eThree (12.5%) showed stable disease\u003c\/li\u003e\n  \u003cli\u003e14 (58.3%) progressed\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eAmong lactotroph tumors, the responses were:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eTwo (16.7%) showed partial response\u003c\/li\u003e\n  \u003cli\u003eFive (41.7%) showed stable disease\u003c\/li\u003e\n  \u003cli\u003eFive (41.7%) progressed\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThus, it is difficult to say whether tumor histological type might play a role.\u003c\/p\u003e\n\n\u003cp\u003eFinally, only four patients with corticotroph tumors had hypercortisolism during ICI administration. Hypercortisolism means high cortisol levels. The numbers are too low to draw any definitive conclusion. Nonetheless, given the immunomodulatory effect of glucocorticoids, it appears prudent to aim for eucortisolism, which means normal cortisol levels.\u003c\/p\u003e\n\n\u003ch3\u003eSide Effects of Immune-Checkpoint Inhibitors\u003c\/h3\u003e\n\u003cp\u003eRegarding immune-related adverse events, as reported also for other cancers, more frequent and more severe adverse events occurred when using combined immunotherapy versus monotherapy. Under combined ICIs, adverse events ranged from mild to severe or even life-threatening.\u003c\/p\u003e\n\n\u003cp\u003eIn addition, combined ipilimumab and nivolumab does not appear so far to be a clear advantage when compared with monotherapy, especially pembrolizumab monotherapy. The revised guidelines consider these to be arguments for initial treatment with PD-1 blockers as monotherapy. However, only six cases treated with pembrolizumab alone are available in the literature.\u003c\/p\u003e\n\n\u003ch3\u003eTreatment Duration and Future Directions for Immunotherapy\u003c\/h3\u003e\n\u003cp\u003eRegarding treatment duration, as with all treatments, this should be a multidisciplinary decision based on effectiveness and tolerability. In the authors' practice, they administer four cycles of combined ipilimumab and nivolumab, followed by maintenance nivolumab for as long as it is well tolerated and remains effective. Similarly, pembrolizumab monotherapy might be continued for as long as it is well tolerated and remains effective. This generally means until progressive disease is noted.\u003c\/p\u003e\n\n\u003cp\u003eHowever, in cases of a dissociate response between lesions in pituitary carcinoma, additional treatments may be added without stopping immunotherapy.\u003c\/p\u003e\n\n\u003cp\u003eThere are two main perspectives regarding immunotherapy. The first is improving the effectiveness of ICIs. The second is using other types of immunotherapies, for example, targeting tumor-associated macrophages or mast cells.\u003c\/p\u003e\n\n\u003cp\u003eRegarding the improvement of ICIs' effectiveness, potential leads include combination therapies, for example, with radiotherapy, peptide receptor radionuclide therapy (PRRT), or anti-angiogenic drugs. Identification and validation of predictors of response, and thus the personalized use of immune-checkpoint inhibitors, will also result in improved observed effectiveness.\u003c\/p\u003e\n\n\u003ch2 id=\"bevacizumab\"\u003eEmerging Option 3: Bevacizumab\u003c\/h2\u003e\n\u003cp\u003eGiven the limited data supporting the use of cytotoxic chemotherapy other than temozolomide and of targeted agents, the revised guidelines recommend participation in clinical studies. This recommendation applies if access to ICIs is difficult and in the absence of a molecular-guided druggable target. Nevertheless, on their algorithm figure, the guidelines include PRRT for tumors with high standardized uptake value (SUV) on 68Ga-DOTA-TOC or 68Ga-DOTA-TATE PET. Otherwise, the guidelines include bevacizumab and\/or conventional chemotherapy.\u003c\/p\u003e\n\n\u003cp\u003eBevacizumab is a monoclonal antibody targeting VEGF-A. VEGF-A is a protein that promotes blood vessel growth. Bevacizumab has been the most commonly used antiangiogenic drug for the treatment of aggressive pituitary tumors and carcinomas.\u003c\/p\u003e\n\n\u003cp\u003eThe tumor response is available for 26 aggressive pituitary tumors and carcinomas. Of these, 14 patients were treated with bevacizumab monotherapy. No clinical trial or large cohort is available for bevacizumab.\u003c\/p\u003e\n\n\u003ch3\u003eHow Well Does Bevacizumab Work?\u003c\/h3\u003e\n\u003cp\u003eRegarding monotherapy, all 14 patients had previously received temozolomide. Most of these 14 patients (57.1%) showed stable disease. There was only one case classified as partial response. Even in this case, there was partial response of the pituitary lesion, while the metastases showed stable disease.\u003c\/p\u003e\n\n\u003cp\u003eFor the four cases treated with bevacizumab combined with first-line temozolomide, the response is quite impressive. This group included one complete response, two partial responses and one stable disease. However, temozolomide itself has quite good effectiveness. Of note, in the case of the complete response, bevacizumab was combined with a Stupp protocol.\u003c\/p\u003e\n\n\u003cp\u003eWhen looking at the response to bevacizumab combined with a second course of temozolomide, the authors encountered one partial response, one stable disease and two progressive diseases. Considering that a second course of temozolomide is more rarely effective, the authors suggest that bevacizumab add-on could provide some benefit. However, this remains to be confirmed on a higher number of patients.\u003c\/p\u003e\n\n\u003cp\u003eFinally, too few cases (four) treated with bevacizumab combined with other chemotherapies are reported to draw any conclusion.\u003c\/p\u003e\n\n\u003ch3\u003ePredictors of Response and Side Effects of Bevacizumab\u003c\/h3\u003e\n\u003cp\u003eVEGF-A\/VEGF receptor immunoreactivity and microvessel density have been associated with a superior response to bevacizumab in a variety of cancers. Unfortunately, data regarding the expression of VEGF and\/or VEGF receptors in the aggressive pituitary tumors and carcinomas treated with bevacizumab have been rarely reported. These data have been inconclusive so far. No data are available on the microvessel density in the treated cases.\u003c\/p\u003e\n\n\u003cp\u003eThe presence or absence of adverse events was rarely reported. Reported adverse events included fatigue, epistaxis (nosebleeds), petechiae (small red spots on the skin), hypertension, nephritis and cellulitis.\u003c\/p\u003e\n\n\u003cp\u003eRegarding treatment duration, as with immunotherapy, the authors administer bevacizumab for as long as it is well tolerated and remains effective.\u003c\/p\u003e\n\n\u003cp\u003eSimilar to immunotherapy, there are two main perspectives: enhancing bevacizumab's effectiveness and exploring alternative antiangiogenic therapies. To boost bevacizumab's performance, strategies such as combining it with chemotherapy or immunotherapy might be considered. Additionally, identifying response predictors for personalized bevacizumab use could further increase its observed effectiveness.\u003c\/p\u003e\n\n\u003ch2 id=\"prrt\"\u003eEmerging Option 4: Peptide Receptor Radionuclide Therapy (PRRT)\u003c\/h2\u003e\n\u003cp\u003eThe principle of PRRT used in aggressive pituitary tumors and carcinomas is the following. A therapeutic radiopharmaceutical is linked to a molecule that targets the tumor. The radiopharmaceutical may be 177Lutetium, 90Yttrium or 68Gallium, of which 177Lutetium has been the most used so far.\u003c\/p\u003e\n\n\u003cp\u003eThe tumor response is available for 31 cases. Of these, the authors analyzed the 20 patients previously treated with temozolomide separately from the 11 patients without previous temozolomide treatment. Of note, no clinical trial or large cohort is available for PRRT.\u003c\/p\u003e\n\n\u003ch3\u003eHow Well Does PRRT Work?\u003c\/h3\u003e\n\u003cp\u003eWhen considering all cases together, partial response was obtained in six cases (19.3%). Eight other patients (25.8%) showed stable disease. Most tumors (54.8%) progressed.\u003c\/p\u003e\n\n\u003cp\u003eHowever, temozolomide-naïve tumors showed a much better response. Among these patients, most tumors (six; 54.5%) showed stable disease, four (36.4%) showed partial response, and only one tumor (9.1%) showed progressive disease.\u003c\/p\u003e\n\n\u003cp\u003eThis better response might be due to different factors. These factors range from publication bias to a potentially less aggressive phenotype of some of the tumors treated with PRRT instead of temozolomide. Nonetheless, whether PRRT should be tried earlier, and maybe even before temozolomide, at least in a subset of aggressive pituitary tumors and carcinomas, is a recurring question. This question is worthy of further studies, especially given that PRRT is currently preferred to chemotherapy at least for a subset of neuroendocrine tumors.\u003c\/p\u003e\n\n\u003ch3\u003ePredictors of Response to PRRT\u003c\/h3\u003e\n\u003cp\u003eRegarding predictors of response, PRRT works by targeting somatostatin receptors on tumor cell membranes. Therefore, one can expect that tumors must express these receptors for the treatment to be effective. Indeed, this seems to be the case, as shown by the available data on somatostatin receptor expression, evaluated by functional imaging, in 16 cases treated with PRRT.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eClinical Implications: What This Means for Patients\u003c\/h2\u003e\n\u003cp\u003eThis review carries several practical messages for patients with aggressive pituitary tumors or pituitary carcinomas. First, temozolomide remains the standard first-line treatment after standard therapy fails. About 40% of patients respond with tumor shrinkage, and one third achieve stable disease. However, one third of patients do not respond, and tumors may recur after treatment stops.\u003c\/p\u003e\n\n\u003cp\u003eSecond, doctors now have several emerging options when temozolomide fails. The choice among these options depends on the tumor's molecular features, the tumor type, and access to the treatments. Molecular testing on a recent tumor tissue sample is now recommended to guide these choices.\u003c\/p\u003e\n\n\u003cp\u003eThird, immune-checkpoint inhibitors have shown the most promise among emerging options. About half of the 38 reported patients had some benefit, including one complete response. Pituitary carcinomas appear to respond better than aggressive pituitary tumors. Combined immunotherapy causes more side effects than monotherapy, which is why the guidelines favor starting with PD-1 blockers as monotherapy.\u003c\/p\u003e\n\n\u003cp\u003eFourth, bevacizumab and PRRT remain options with more limited data. Bevacizumab produced stable disease in most patients treated as monotherapy. PRRT produced the best results in patients who had not previously received temozolomide.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations: What This Review Could Not Prove\u003c\/h2\u003e\n\u003cp\u003eThis review has several important limitations that patients and doctors should keep in mind. Most evidence for emerging treatments comes from case reports and small cohorts, not from large randomized trials. No clinical trial or large cohort is available for bevacizumab. No clinical trial or large cohort is available for PRRT either.\u003c\/p\u003e\n\n\u003cp\u003eDifferent studies or case reports have evaluated tumor response differently. The duration of response is also variable across reports. This makes direct comparisons between treatments difficult.\u003c\/p\u003e\n\n\u003cp\u003ePredictors of response remain uncertain. MGMT status has shown inconsistent results as a predictor of temozolomide response. Tumor mutational burden and mismatch repair deficiency appear promising for ICIs, but not all cases with these features responded. Data on VEGF expression in tumors treated with bevacizumab have been rarely reported and inconclusive.\u003c\/p\u003e\n\n\u003cp\u003eWhether temozolomide-induced hypermutation carries the same risks in pituitary tumors as in low-grade gliomas has not been investigated yet. Whether PRRT should be used before temozolomide remains an open question that requires further studies.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations and Practical Advice\u003c\/h2\u003e\n\u003cp\u003eBased on this review and the revised European Society of Endocrinology guideline, patients and their care teams can consider the following points:\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003eRepeat surgery by an expert neurosurgeon and radiotherapy remain core treatments for aggressive pituitary tumors and carcinomas.\u003c\/li\u003e\n  \u003cli\u003eConventional pituitary-directed medical treatments should be used at maximally tolerated doses. These include somatostatin receptor ligands and cabergoline, depending on the tumor type.\u003c\/li\u003e\n  \u003cli\u003eEarly adjuvant radiotherapy may be considered for patients with residual tumor and pathological or molecular markers of aggressiveness, even before aggressive behavior is proved.\u003c\/li\u003e\n  \u003cli\u003eTemozolomide is the first-line treatment after standard therapy failure. Doctors should reassess the tumor after three cycles and stop treatment in non-responders with progression.\u003c\/li\u003e\n  \u003cli\u003eMolecular testing on a recent tumor tissue sample is recommended for patients with tumor progression on temozolomide. A minimal invasive surgical biopsy may be considered to obtain this tissue.\u003c\/li\u003e\n  \u003cli\u003eImmune-checkpoint inhibitors may be considered for patients with pituitary carcinoma and rapid tumor progression after temozolomide. PD-1 blocker monotherapy is favored as the initial approach because combined immunotherapy causes more side effects.\u003c\/li\u003e\n  \u003cli\u003eIf access to ICIs is difficult and no molecular-guided druggable target is found, participation in clinical studies is recommended.\u003c\/li\u003e\n  \u003cli\u003ePRRT may be considered for tumors with high standardized uptake value on 68Ga-DOTA-TOC or 68Ga-DOTA-TATE PET. Otherwise, bevacizumab and\/or conventional chemotherapy may be considered.\u003c\/li\u003e\n  \u003cli\u003eFor patients with oligo-metastatic disease, loco-regional therapies such as surgery, radiotherapy, ablation, or embolization may be used alone or combined with systemic treatment.\u003c\/li\u003e\n  \u003cli\u003eTreatment duration for all therapies should be a multidisciplinary decision based on effectiveness and tolerability.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003ePatients with corticotroph tumors who have hypercortisolism during immunotherapy may benefit from aiming for normal cortisol levels, given the immunomodulatory effect of glucocorticoids. However, the numbers of such patients are too low to draw any definitive conclusion.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is temozolomide and why is it the first treatment offered?\u003c\/h3\u003e\n\u003cp\u003eTemozolomide is an oral pill that damages tumor cell DNA. Guidelines recommend it first after standard therapy fails and tumor growth is documented. About 40% of patients see complete or partial tumor shrinkage, and one third have stable disease. However, one third progress on it, and tumors may recur after treatment stops.\u003c\/p\u003e\n\u003ch3\u003eHow will my doctor know if temozolomide is working?\u003c\/h3\u003e\n\u003cp\u003eDoctors reassess the tumor after three cycles. If the tumor has progressed by then, treatment should stop. For patients who respond, guidelines recommend continuing temozolomide monotherapy for 12 months, with longer treatment considered to obtain a maximal response if side effects are absent.\u003c\/p\u003e\n\u003ch3\u003eWhat are immune-checkpoint inhibitors and who might be offered them?\u003c\/h3\u003e\n\u003cp\u003eThese drugs block the immune system's brakes to help it attack the tumor. Guidelines suggest considering them for patients with pituitary carcinoma and rapid tumor progression after temozolomide. Among 38 reported cases, about half had some benefit, including one complete response. Pituitary carcinomas responded better than aggressive pituitary tumors.\u003c\/p\u003e\n\u003ch3\u003eAre immune-checkpoint inhibitors given alone or combined?\u003c\/h3\u003e\n\u003cp\u003eBoth approaches have been used. Combined ipilimumab plus nivolumab caused more frequent and more severe side effects than monotherapy, and so far shows no clear advantage over pembrolizumab alone. Guidelines therefore favor starting with PD-1 blocker monotherapy. Only six cases treated with pembrolizumab alone are available in the literature.\u003c\/p\u003e\n\u003ch3\u003eWhat is PRRT and when might it be considered?\u003c\/h3\u003e\n\u003cp\u003ePRRT delivers radiation directly to tumor cells by targeting somatostatin receptors. Guidelines include it for tumors with high uptake on specific PET scans. Among 31 reported cases, tumors not previously treated with temozolomide responded better: 54.5% stable disease and 36.4% partial response. No clinical trial or large cohort is available.\u003c\/p\u003e\n\u003ch3\u003eWhy is molecular testing recommended after temozolomide fails?\u003c\/h3\u003e\n\u003cp\u003eMolecular testing on a recent tumor tissue sample may reveal specific gene alterations that can be targeted, plus tumor mutational burden and mismatch repair status. Guidelines recommend it for patients progressing on temozolomide. A minimal invasive surgical biopsy may be considered to obtain this tissue, since one patient's mutation appeared only in a later sample.\u003c\/p\u003e\n\u003ch3\u003eWhen should a patient with an aggressive pituitary tumor or pituitary carcinoma seek a second opinion?\u003c\/h3\u003e\n\u003cp\u003eA second opinion is worth considering when temozolomide is proposed or has failed. Temozolomide is first-line after standard therapy, with about 40% of patients showing tumor shrinkage and one third stable disease, but one third progress. When it fails, the choice among molecular-guided targeted drugs, immune-checkpoint inhibitors, bevacizumab, and peptide receptor radionuclide therapy depends on the tumor's molecular features, tumor type, and treatment access, and molecular testing on a recent tissue sample guides these choices. Because most evidence for emerging options comes from case reports and small cohorts, an independent review of pathology and imaging can help clarify options. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Therapy for aggressive pituitary tumors and carcinomas.\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Ilie MD, Lamback E, Gadelha M, Raverot G.\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor affiliations:\u003c\/strong\u003e \"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania; Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil; Inserm U1052, CNRS UMR5286, Claude Bernard Lyon 1 University, Cancer Research Center of Lyon, Lyon, France; Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, \"Groupement Hospitalier Est\" Hospices Civils de Lyon, Bron, France\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication details:\u003c\/strong\u003e Reviews in Endocrine and Metabolic Disorders (2026) 27:781–790. https:\/\/doi.org\/10.1007\/s11154-026-10039-4. Received: 4 February 2026. Accepted: 8 April 2026. Published online: 17 April 2026.\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eKeywords:\u003c\/strong\u003e Aggressive pituitary tumor, Pituitary carcinoma, Temozolomide, Immune-checkpoint inhibitors, Bevacizumab, Peptide receptor radionuclide therapy\u003c\/p\u003e\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47816835072156,"sku":null,"price":0.0,"currency_code":"KRW","in_stock":true}],"url":"https:\/\/diagnosticdetectives.kr\/products\/new-and-established-treatments-for-aggressive-pituitary-tumors-and-pituitary-carcinomas-a-guide-for-patients","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}